Flucostat, 150 mg capsules

Pharmacodynamics:

Fluconazole, a member of the triazole antifungal class, is a selective inhibitor of sterol synthesis in the fungal cell.

Fluconazole has demonstrated activity in-vitro and in clinical studies against most of the following microorganisms: Candidaalbicans, Candidaglabrata (many strains are moderately sensitive), Candidaparapsilosis, Candidatropicalis, Cryptococcusneoformans.

The activity of fluconazole against the following microorganisms has been shown, but its clinical significance is not known: Candidadubliniensis, Candidaguilliermondii, Candidakefyr, Candidalusitaniae.

In oral administration, fluconazole shows activity in various models of fungal infections in animals. It has demonstrated activity against opportunistic mycoses including those caused by Candidaspp. (including generalized candidiasis in immunocompromised animals), Cryptococcus neoformans (including intracranial infections), Microsporumspp. and Trychophytonspp.

Fluconazole has high specificity against cytochrome P450-dependent fungal enzymes. Fluconazole therapy at a dose of 50 mg/day for up to 28 days has no effect on plasma testosterone concentrations in men or steroid concentrations in women of childbearing age.

Fluconazole at a dose of 200 to 400 mg/day has no clinically significant effect on endogenous steroid levels and their response to adrenocorticotropic hormone (ACTH) stimulation in healthy male volunteers.

Mechanisms of Fluconazole Resistance

Resistance to fluconazole can develop in the following cases: a qualitative and quantitative change in the enzyme that targets fluconazole (lanosterol 14-α-demethylase), reduced access to the target fluconazole, or a combination of these mechanisms.

Point mutations in the ERG11 gene, which encodes the target enzyme, lead to target alteration and decreased affinity for azoles. Increased expression of the ERG11 gene leads to production of high concentrations of the target enzyme, which creates a need for increased fluconazole concentrations in the intracellular fluid to inhibit all enzyme molecules in the cell.

The second significant mechanism of resistance is the active excretion of fluconazole from the intracellular space through the activation of two types of transporters involved in the active excretion (efflux) of the drugs from the fungal cell.

These transporters include a major mediator encoded by the MDR (multidrug resistance) genes and an ATP-binding cassette transporter superfamily encoded by the CDR genes (Candida fungi resistance genes to azolovymantimycotics).

Hyperexpression of the MDR gene leads to resistance to fluconazole, while hyperexpression of CDR genes can lead to resistance to various azoles.

Resistance to Candidaglabrata is usually mediated by CDR gene overexpression, which leads to resistance to many azoles. For those strains in which the minimum inhibitory concentration (MIC) is defined as intermediate (16-32 µg/ml), maximum doses of fluconazole are recommended.

Candidacrosis should be considered resistant to fluconazole. The mechanism of resistance is associated with reduced sensitivity of the target enzyme to the inhibitory effects of fluconazole.

Pharmacokinetics:

Fluconazole pharmacokinetics are similar with intravenous and oral administration. After oral administration fluconazole is well absorbed, its plasma concentrations (and overall bioavailability) exceed 90% of those of intravenous administration.

Concurrent intake of food does not affect absorption of the drug taken orally. The plasma concentration is proportional to the dose and reaches a maximum (C_max) in 0.5-1.5 hours after fluconazole is taken on an empty stomach, and the elimination half-life is about 30 hours.

The maximum concentration of fluconazole in saliva when taking the capsule is reached after 4 hours.

The volume of distribution is close to the total water content in the body. Binding to plasma proteins is low (11-12%).

Fluconazole penetrates well into all body fluids. Concentrations of the drug in saliva and sputum are similar to its levels in blood plasma.

In the stratum corneum, epidermis, dermis and sweat fluids, high concentrations are achieved that exceed serum levels.

Fluconazole accumulates in the stratum corneum. When taken at a dose of 50 mg once daily, fluconazole concentrations are 73 µg/g after 12 days and only 5.8 µg/g after 7 days of discontinuation of treatment. When used in a dose of 150 mg once a week, the concentration of fluconazole in the stratum corneum on day 7 is 23.4 µg/g, and 7 days after the second dose is 7.1 µg/g.

The concentration of fluconazole in the nails after 4 months of use at a dose of 150 mg once a week is 4.05 in healthy nails and 1.8 µg/g in affected nails; 6 months after completion of therapy, fluconazole is still detectable in the nails.

Fluconazole is mainly excreted by the kidneys; approximately 80% of the administered dose is excreted unchanged. Fluconazole clearance is proportional to creatinine clearance. No fluconazole metabolites were detected in peripheral blood.

The long plasma elimination half-life allows fluconazole to be taken once for vaginal candidiasis.

Pharmacokinetics in elderly patients

It was found that with a single oral dose of fluconazole 50 mg in elderly patients aged 65 years and older, some of whom were also taking diuretics, C_max was reached 1.3 h after administration and was 1.54 µg/mL, the mean AUC (area under the concentration-time curve) was 76.4 ± 20.3 µg×h/mL, and the mean half-life was 46.2 h.

The values of these pharmacokinetic parameters are higher than in younger patients, which is probably due to the reduced renal function characteristic of older age. Concomitant administration of diuretics did not cause significant changes in AUC and C_max.

Creatinine clearance (74 ml/min), the percentage of fluconazole excreted unchanged by the kidneys (0-24 h, 22%) and the renal clearance of fluconazole (0.124 ml/min/kg) are lower in elderly patients compared to younger patients.

Indications

Fungus, Lymphoma (candidiasis), Itching and dryness in the genital area, Skin itching, Skin fungus, Nail fungusTreatment of acute vaginal candidiasis when local therapy is not applicable.

Active ingredient

Fluconazole

Composition

Active ingredient:

fluconazole 50 mg or 150 mg;

excipients: lactose (milk sugar) 49.40 mg or 147.40 mg, corn starch 16.40 mg or 49.00 mg, colloidal silica (aerosil) 0.12 mg or 0.36 mg, magnesium stearate 0.96 mg or 2.88 mg, sodium lauryl sulfate 0.12 mg or 0.36 mg;

Solid gelatin capsules:

(for 50 mg dosage) body: titanium dioxide (E 171) – 3.0000%, iron oxide red (E 172) – 0.0857%, gelatin – up to 100%; lid: titanium dioxide (E 171) – 2.0000 %, iron oxide red (E 172) – 0.7286 %, gelatin – up to 100 %;

(for 150 mg dosage) case and cap: titanium dioxide (E 171) – 2.0000 %, gelatin – up to 100 %.

How to take, the dosage

Ingestion. The capsules are swallowed whole.

In acute vaginal candidiasis the drug is used once orally in a dose of 150 mg.

Use in the elderly

In elderly patients in the absence of renal dysfunction, the usual dosing regimen of the drug should be followed.

Use in patients with renal impairment

There is no need to change the dose on a single dose.

Interaction

Single or multiple administration of fluconazole in a dose of 50 mg does not affect the metabolism of fenazone (Antipyrine) when they are taken alone.

The simultaneous use of fluconazole with the following drugs is contraindicated:

Cisapride. Concomitant use of fluconazole and cisapride may cause adverse cardiac reactions, including torsadedepointes ventricular tachysystolic arrhythmia. Fluconazole administration in dose 200 mg once daily and cisapride in dose 20 mg four times daily causes significant increase of plasma concentration of cisapride and QT interval prolongation on ECG.

The concomitant use of cisapride and fluconazole is contraindicated.

Terfenadine. Concomitant use of azole antifungal agents and terfenadine may cause serious arrhythmias due to prolongation of the QT interval. When fluconazole was administered at a dose of 200 mg/day it was not established an increase in the QT interval.

But fluconazole administration in doses of 400 mg/day and higher causes significant increase in terfenadine plasma concentrations. Concomitant use of fluconazole in doses of 400 mg/day or more with terfenadine is contraindicated (see section “Contraindications”). Treatment with fluconazole in doses less than 400 mg/day in combination with terfenadine should be performed under close supervision.

Astemizole. Concomitant use of fluconazole with astemizole or other drugs, metabolized by cytochrome P450 system, may be accompanied by increased serum concentrations of these drugs. Increased concentrations of astemizole in blood plasma may lead to prolongation of QT interval and in some cases to development of ventricular tachycardia of “pirouette” type (torsadedepointes). Simultaneous use of astemizole and fluconazole is contraindicated.

Pimozide. Although no in-vitro or in-vivo studies have been performed, concomitant use of fluconazole and pimozide may lead to inhibition of pimozide metabolism.

In turn, increased plasma concentrations of pimozide may lead to prolongation of the QT interval and, in some cases, development of torsadedepointes ventricular tachycardia. Simultaneous use of pimozide and fluconazole is contraindicated.

Hinidine. Although appropriate in-vitro or in-vivo studies have not been conducted, concomitant use of fluconazole and quinidine may also lead to inhibition of quinidine metabolism. The use of quinidine is associated with prolongation of the QT interval and in some cases with the development of torsadedepointes ventricular tachycardia. Simultaneous use of quinidine and fluconazole is contraindicated.

Eritromycin. Concomitant use of fluconazole and erythromycin potentially leads to an increased risk of cardiotoxicity (prolongation of QT interval, torsadedepointes) and, consequently, sudden cardiac death. Simultaneous use of fluconazole and erythromycin is contraindicated.

Amiodarone. Concomitant use of fluconazole and amiodarone may lead to inhibition of amiodarone metabolism. Amiodarone use has been associated with prolongation of the QT interval. Concomitant use of fluconazole and amiodarone is contraindicated (see section “Contraindications”).

Caution should be exercised and doses may need to be adjusted if the following drugs and fluconazole are used concomitantly:

Drugs affecting fluconazole:

Hydrochlorothiazide. Simultaneous repeated use of fluconazole and hydrochlorothiazide may increase fluconazole plasma concentrations by 40%. This effect does not require modification of fluconazole dosing regimen in patients receiving concomitant diuretics, but the physician should consider this.

Rifampicin. Combination with rifampicin decreases AUC (area under curve “concentration-time”) by 25% and shortens half-life of fluconazole from plasma by 20%. Therefore, in patients receiving rifampicin concomitantly, it is necessary to consider the advisability of increasing the dose of fluconazole.

Drugs affected by fluconazole:

Fluconazole is a potent inhibitor of CYP2C9 and CYP2C19 cytochrome P 450 isoenzyme and a moderate inhibitor of CYP3A4 isoenzyme. In addition to the effects listed below, there is a risk of increased plasma concentrations of other drugs metabolized by CYP2C9, CYP2C19 and CYP3A4 isoenzymes when concomitantly administered with fluconazole.

In this regard, caution should be exercised when using the following drugs concomitantly, and patients should be under close medical supervision if such combinations are necessary. It should be noted that the inhibitory effect of fluconazole persists for 4-5 days after discontinuation of the drug due to a long half-life.

Alfentanil. Decrease of clearance and volume of distribution and increase of half-life of alfentanil have been noted. This may be due to inhibition of CYP3A4 isoenzyme by fluconazole. Dose adjustment of alfentanil may be required.

Amitriptyline, nortriptyline. Increased effect. The concentration of 5-nortriptyline and/or S-amitriptyline can be measured at the beginning of combined therapy with fluconazole and one week after the start of treatment. The dose of amitriptyline/nortriptyline should be adjusted if necessary.

Amphotericin B. In studies in mice (including those with immunosuppression) the following results were observed: a small additive antifungal effect in systemic infection caused by C. albicans, no interaction in intracranial infection caused by Cryptococcusneoformans and antagonism in systemic infection caused by A. fumigatus. The clinical significance of these results is unclear.

Anticoagulants.When using fluconazole, as well as other antifungal agents (azole derivatives), with warfarin increases prothrombin time (on average by 12%).

The development of bleeding (hematoma, bleeding from the nose and gastrointestinal tract, hematuria, melena) is possible. In patients receiving coumarin anticoagulants it is necessary to monitor prothrombin time during the therapy and within 8 days after concomitant use. The appropriateness of warfarin dose adjustment should also be evaluated.

Asithromycin. No significant pharmacokinetic interaction between fluconazole in a single dose of 800 mg and azithromycin in a single dose of 1200 mg was found in concomitant use of both drugs.

Benzodiazepines (short-acting). After oral administration of midazolam, fluconazole significantly increases midazolam concentration and psychomotor effects, and this effect is more pronounced after fluconazole oral administration than when it is used intravenously. If concomitant therapy with benzodiazepines is necessary, patients taking fluconazole should be monitored to assess the appropriateness of an appropriate reduction in the benzodiazepine dose.

On concomitant administration of a single dose of triazolam, fluconazole increases the AUC of triazolam by approximately 50%, the C_max by 25-50% and the elimination half-life by 25-50% due to inhibition of triazolam metabolism. Dose adjustment of triazolam may be necessary.

Carbamazepine.Fluconazole inhibits the metabolism of carbamazepine and increases its serum concentration by 30%. The risk of carbamazepine toxicity should be considered. The need for carbamazepine dose adjustment depending on the concentration/effect should be assessed.

Nevirapine.Co-administration of fluconazole and nevirapine increases exposure to nevirapine by approximately 100% compared with control data for separate use of nevirapine. Because of the risk of increased nevirapine excretion with concomitant medication use, some precautions and close monitoring of patients is necessary.

Calcium channel blockers. Some calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by CYP3A4 isoenzyme. Fluconazole increases systemic exposure to calcium channel antagonists. Control of side effects is recommended.

Cyclosporine. It is recommended to monitor the blood concentration of cyclosporine in patients receiving fluconazole, because in patients with kidney transplantation the administration of fluconazole at a dose of 200 mg/day leads to a slow increase in plasma concentration of cyclosporine. However, no change in cyclosporine concentrations was observed in bone marrow recipients when fluconazole was administered repeatedly at a dose of 100 mg/day.

Cyclophosphamide. When concomitant use of cyclophosphamide and fluconazole an increase in serum concentrations of bilirubin and creatinine is observed. Combination of drugs is possible taking into account the risk of these disorders.

Fentanyl. One fatality has been reported, possibly associated with concomitant administration of fentanyl and fluconazole. The abnormalities are thought to be related to fentanyl intoxication. Fluconazole has been shown to significantly prolong fentanyl elimination time. Note that increased fentanyl concentrations may result in respiratory depression.

Halofantrine.Fluconazole may increase plasma concentrations of halofantine due to inhibition of the CYP3A4 isoenzyme. Concomitant use with fluconazole as well as with other antifungal drugs of azole type may cause ventricular tachycardic “pirouette” arrhythmia, therefore joint use is not recommended.

HMK-CoA reductase inhibitors. Co-administration of fluconazole with HMCC-CoA reductase inhibitors, metabolized by CYP3A4 isoenzyme (such as atorvastatin and simvastatin) or CYP2D6 isoenzyme (fluvastatin) increases risk of myopathy and rhabdomyolysis. If concomitant therapy with these drugs is necessary, patients should be monitored for symptoms of myopathy and rhabdomyolysis.

Creatinine kinase concentration should be monitored. If creatinine kinase concentration increases significantly or if myopathy or rhabdomyolysis is diagnosed or suspected, therapy with HMK-CoA reductase inhibitors should be discontinued.

Lozartan.Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74), which is responsible for most of the effects associated with angiotensin II receptor antagonism. Regular monitoring of blood pressure is necessary.

Methadone.Fluconazole may increase the plasma concentration of methadone. Adjustment of the methadone dose may be necessary.

Non-steroidal anti-inflammatory drugs (NSAIDs).The C_max and AUC of flurbiprofen are increased by 23% and 81%, respectively. Similarly, the C_max and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was used concomitantly with racemic ibuprofen (400 mg).

The concomitant use of fluconazole at a dose of 200 mg/day and celecoxib at a dose of 200 mg increased C_max and AUC of celecoxib by 68 % and 134 %, respectively. In this combination, it is possible to reduce the dose of celecoxib by half.

While there are no focused studies, fluconazole may increase systemic exposure to other NSAIDs metabolized by CYP2C9 isoenzyme (naproxen, lornoxicam, meloxicam, diclofenac). Dose adjustment of NSAIDs may be necessary.

When concomitant use of NSAIDs and fluconazole patients should be closely monitored by a physician to identify and control adverse events and manifestations of NSAID-related toxicity.

The oral contraceptives. No significant effects on hormone levels have been found when combined oral contraceptives and fluconazole in a dose of 50 mg are used concomitantly. The AUCs of ethinylestradiol and levonorgestrel are increased by 40% and 24%, respectively, when taking fluconazole 200 mg daily. When taking 300 mg of fluconazole once a week, the AUCs of ethinylestradiol and norethindrone increase by 24% and 13%, respectively. Thus, repeated use of fluconazole at these doses is unlikely to affect the efficacy of the combined oral contraceptive.

Phenytoin. Concomitant use of fluconazole and phenytoin may increase plasma concentrations of phenytoin to clinically significant levels. Therefore, if co-administration of these drugs is necessary, phenytoin concentrations should be monitored with dose adjustments to maintain drug levels within the therapeutic interval.

Prednisone. There is a report of acute adrenal cortical insufficiency in a patient after liver transplantation on withdrawal of fluconazole after three months of therapy. Presumably, discontinuation of fluconazole therapy caused increased CYP3A4 isoenzyme activity, which resulted in increased metabolism of prednisone.

Patients receiving combined therapy with prednisone and fluconazole should be closely monitored during discontinuation of fluconazole to assess the adrenal cortex.

Rifabutin. Concomitant use of fluconazole and rifabutin may increase serum concentrations of the latter up to 80%. There have been cases of uveitis during concomitant use of fluconazole and rifabutin. Patients receiving rifabutin and fluconazole concomitantly should be closely monitored.

Sacquinavir. AUC is increased by approximately 50%, C_max by 55%. Clearance of saquinavir is decreased by approximately 50% due to inhibition of hepatic metabolism of CYP3A4 isoenzyme and P-glycoprotein. Dose adjustment of saquinavir may be necessary.

Sirolimus. Increased plasma concentrations of sirolimus are thought to be due to inhibition of sirolimus metabolism through inhibition of CYP3A4 isoenzyme and P-glycoprotein. This combination can be used with appropriate dose adjustment of sirolimus depending on the effect/concentration.

Sulfonylurea drugs.Fluconazole increases plasma elimination half-life of oral hypoglycemic agents – sulfonylurea derivatives (chlorpropamide, glibenclamide, glipizide, tolbutamide). Concomitant use of fluconazole and oral hypoglycemic agents is allowed, but the physician should keep in mind the possibility of hypoglycemia. Regular control of blood glucose and, if necessary, dose adjustment of sulfonylureas is necessary.

Tacrolimus. Administration of fluconazole and tacrolimus (orally) leads to increase of serum concentrations of the latter by 5 times due to inhibition of tacrolimus metabolism, which occurs in intestine through CYP3A4 isoenzyme. No significant changes in pharmacokinetics of the drugs were observed when using tacrolimus intravenously. Cases of nephrotoxicity have been described. Patients receiving oral tacrolimus and fluconazole concomitantly should be closely monitored. The dose of tacrolimus should be adjusted according to the degree of increase in its blood concentration.

Theophylline. In concomitant use with fluconazole at a dose of 200 mg for 14 days the average plasma clearance rate of theophylline is decreased by 18%. When fluconazole is administered to patients taking theophylline in high doses, or to patients with increased risk of development of toxic effect of theophylline, the appearance of symptoms of theophylline overdose should be monitored and if necessary, the therapy should be adjusted accordingly.

The periwinkle alkaloid. Although there are no focused studies, it has been suggested that fluconazole may increase plasma concentrations of barvinac alkaloids (e.g., vincristine and vinblastine) and thus lead to neurotoxicity, which may be due to inhibition of the CYP3A4 isoenzyme.

Vitamin A. One case of adverse central nervous system (CNS) reactions in the form of pseudotumor of the brain has been reported with the simultaneous use of completely transretinoic acid and fluconazole, which disappeared after withdrawal of fluconazole. The use of this combination is possible, but it should be remembered about the possibility of adverse reactions from the CNS.

Zidovudine. In patients receiving fluconazole and zidovudine combination there is an increase in Cmax and AUC of zidovudine by 84% and 74% respectively, which is caused by decrease of zidovudine metabolism to its main metabolite. Before and after treatment with fluconazole at a dose of 200 mg/day for 15 days in patients with AIDS and ARC (AIDS-related complex) a significant increase in AUC of zidovudine (20%) was found. Patients receiving this combination should be monitored to detect side effects of zidovudine.

Voriconazole (inhibitor of CYP2C9, CYP2C19 and CYP3A4 isoenzymes). Concomitant administration of voriconazole (400 mg twice daily on the first day, then 200 mg twice daily for 2.5 days) and fluconazole (400 mg on the first day, then 200 mg daily for 4 days) causes increase of concentration and AUC of voriconazole by 57% and 79% respectively.

This effect has been shown to persist with a reduction in the dose and/or frequency of administration of either drug. Simultaneous use of voriconazole and fluconazole is not recommended.

Tofacitinib. Exposure of tofacitinib is increased when it is coadministered with drugs that are both moderate inhibitors of CYP3A4 and potent inhibitors of CYP2C19 isoenzyme (e.g., fluconazole). It may be necessary to adjust the dose of tofacitinib.

Ivacaftor. When used concomitantly with ivacaftor, a stimulator of cystic fibrosis transmembrane conductance regulator (CFTR), a 3-fold increase in ivacaftor exposure and a 1.9-fold increase in hydroxymethyl ivacaftor (M1) exposure were observed. In patients concomitantly taking CYP3A inhibitors, such as fluconazole and erythromycin, it is recommended to reduce the dose of ivacaftor to 150 mg once daily.

The studies of oral fluconazole interaction when taken concomitantly with food, cimetidine, antacids, and after total body irradiation in preparation for bone marrow transplantation showed that these factors have no clinically significant effect on fluconazole absorption.

The listed interactions have been established with repeated administration of fluconazole; there are no known drug-drug interactions as a result of single administration of fluconazole.

Physicians should note that interactions with other medicinal products have not been specifically studied, but are possible.

Special Instructions

When using fluconazole 150 mg for vaginal candidiasis, patients should be warned that improvement in symptoms is usually seen after 24 hours, but it sometimes takes several days for symptoms to disappear completely. If symptoms persist for several days, a doctor should be consulted.

In rare cases, the use of fluconazole has been accompanied by toxic liver changes, including fatalities, mainly in patients with severe comorbidities.

In the case of hepatotoxic effects associated with fluconazole, no clear dependence on the total daily dose, duration of therapy, sex and age of the patient was noted. Hepatotoxic effects of fluconazole were usually reversible; signs of them disappeared after discontinuation of therapy.

Patients who have liver function abnormalities during treatment with the drug should be monitored to detect signs of more serious liver damage. If there are clinical signs or symptoms of liver damage that may be associated with fluconazole use, the drug should be discontinued.

As with other azoles, fluconazole may cause anaphylactic reactions in rare cases.

In rare cases, exfoliative skin lesions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have developed during treatment with fluconazole.

AIDS patients are more prone to develop severe skin reactions when using many drugs. In cases where patients with superficial fungal infections develop a rash and it is considered definitely related to fluconazole, the drug should be discontinued.

When rashes occur in patients with invasive/systemic fungal infections, they should be closely monitored and fluconazole should be discontinued if bullous changes or erythema multiforme exudative.

The concomitant use of fluconazole in doses less than 400 mg/day and terfenadine should be carefully controlled (see section “Interaction with other medicinal products”).

In common with other azoles, fluconazole may cause prolongation of QT interval on ECG. During fluconazole use, QT interval prolongation and ventricular fibrillation or flutter have been observed very rarely in patients with severe diseases with multiple risk factors, such as organic heart disease, electrolyte imbalance, and concomitant therapy contributing to such disorders. Therefore, in these patients with potentially proarrhythmic conditions, fluconazole should be used with caution.

Patients with liver, heart and kidney disease are advised to consult a physician before using the drug.

There have been reported cases of superinfections caused by Candida strains other than Candidaalbicans, which are often naturally resistant to fluconazole (e.g., Candidakrusei). In such cases, alternative antifungal therapy may be necessary.

Impact on ability to drive vehicles and mechanisms

Due to the possibility of dizziness and other side effects associated with taking the drug, during the treatment period patients are advised to refrain from driving and engaging in other potentially dangerous activities requiring increased concentration, rapid psychomotor and motor reactions.

Contraindications

– Concomitant use of terfenadine (with multiple fluconazole doses of 400 mg/day or more) (see “Interaction with other medicinal products.

– Hypersensitivity to fluconazole and other components of the drug or similar azole compounds;

– Children under 18 years of age;

– Period of lactation (see section “Use during pregnancy and breast-feeding.

– Concomitant use with drugs that increase the QT interval and are metabolized with CYP3A4 isoenzyme, such as cisapride, astemizole, erythromycin, pimozide, quinidine and amiodarone (see “Interaction with other compounds”).

Galactose intolerance, lactase deficiency, glucose-galactose malabsorption.

With caution

– Impaired liver function;

– Concurrent use of potentially hepatotoxic drugs;

– Alcoholism;

– Proarrhythmogenic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalances, concurrent use of drugs that cause arrhythmias);

– Impaired renal function;

– Rash on fluconazole in patients with superficial fungal infection and invasive/systemic fungal infections;

– Concurrent use of terfenadine and fluconazole at a dose less than 400 mg/day.

Side effects

Classification of adverse reactions by organ and system is given by frequency of occurrence: Very common (≥1/10); common (≥1/100, < 1/10); infrequent (≥1/1000, < 1/100); rare (≥1/10000, < 1/1000); very rare (< 1/10000), including individual reports whose frequency is unknown (frequency cannot be estimated from available data). Tolerability of the drug is generally very good. The following adverse reactions have been reported in clinical and post-marketing (*) studies of fluconazole:

Nervous system disorders: frequently, headache; infrequently, dizziness*, seizures*, change in taste*, paresthesia, insomnia, somnolence; rarely, tremor.

Gastro-intestinal disorders: frequently – abdominal pain, diarrhea, vomiting*, nausea; infrequently – flatulence, dyspepsia*, dry oral mucosa, constipation.

Liver and biliary tract disorders: frequent – increased serum aminotransferase activity (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), alkaline phosphatase; infrequent – jaundice*, cholestasis, increased bilirubin concentration; rare – hepatotoxicity, in some cases with fatal outcome, liver dysfunction*, hepatitis*, hepatocellular necrosis*, hepatocellular damage.

Dermal and

Subcutaneous and subcutaneous fatty tissue disorders: Frequent – rash; infrequent – skin itching, urticaria, increased sweating, drug-induced rash; rare – exfoliative skin lesions*, including Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis, facial edema, alopecia*.

Blood and lymphatic system disorders*: rarely – leukopenia, including neutropenia and agranulocytosis, thrombocytopenia, anemia.

Disorders of the immune system*: rarely – anaphylaxis (including angioedema, facial edema).

Cardiovascular system disorders*: rarely – prolongation of the QT interval in the ECG, pirouette-type ventricular tachycardia (see section “Cautions”).

Metabolic disorders*: rarely – increased concentration of cholesterol and triglycerides in plasma, hypokalemia.

Musculoskeletal system disorders: infrequent – myalgia.

Others: infrequent – weakness, asthenia, fatigue, fever, vertigo.

In some patients, especially those with serious illnesses such as HIV infection or cancer, changes in blood counts, renal function and liver function have been observed during treatment with fluconazole and similar drugs, but the clinical significance of these changes and their relationship to treatment have not been established.

If any of the side effects listed in the instructions are aggravated, or if any other side effects not listed in the instructions are noted, the physician should be informed immediately.

Overdose

Symptoms: hallucinations, paranoid behavior.

Treatment: symptomatic, gastric lavage, forced diuresis.

Hemodialysis within 3 hours reduces plasma concentrations by approximately 50%.

Pregnancy use

There are no adequate and controlled studies of fluconazole use in pregnant women.

There is currently no evidence that low doses of fluconazole (150 mg once for the treatment of vulvovaginal candidiasis) have an increased incidence of adverse pregnancy outcomes, or a relationship to any specific malformations in the child.

High doses (400-800 mg/day) of fluconazole have described several cases of multiple birth defects in infants whose mothers received fluconazole therapy for most or all of the first trimester.

The use of the drug in pregnant women is not advisable, except for severe or life-threatening forms of fungal infections, if the anticipated benefit to the mother exceeds the possible risk to the fetus.

Women of childbearing age should use contraception.

Fluconazole is present in breast milk at the same concentration as in plasma, so it is contraindicated during lactation.

Similarities

Diflucan, Flucostat, Mycosist, Mycomax, Fluconazole-Teva, Fluconazole, Fluconazole Stada, Fluconazole Sandoz