Flucostat, capsules 50mg, 7pcs

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 silicon dioxide (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 dosage 50 mg) case: 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%.

Pharmacological action

Pharmacodynamics :

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

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

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

When taken orally, fluconazole is active in various models of fungal infections in animals. The drug has been shown to be active in opportunistic mycoses, including those caused by Candidaspp. (including generalized candidiasis in immunocompromised animals), Cryptococcus Neoformans (including intracranial infections), Microsporumspp. and Trychophytonspp.

Fluconazole is highly specific for cytochrome P 450-dependent fungal enzymes. Fluconazole therapy at a dose of 50 mg / day for up to 28 days does not affect the concentration of testosterone in the blood plasma in men or the concentration of steroids in women of childbearing age.

Fluconazole at a dose of 200-400 mg / day does not have a clinically significant effect on the levels of endogenous steroids and their response to stimulation of adrenocorticotropic hormone (ACTH) in healthy male volunteers.

Mechanisms of development of resistance to fluconazole

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

Point mutations in the ERG11 gene encoding the target enzyme lead to a modification of the target and a decrease in affinity for azoles. An increase in the expression of the ERG11 gene leads to the production of high concentrations of the target enzyme, which creates the need to increase the concentration of fluconazole in the intracellular fluid to suppress all enzyme molecules in the cell.

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

These transporters include the main intermediary encoded by MDR (multiple drug resistance) genes, and the superfamily of ATP-binding cassette transporters encoded by CDR (Candida fungal resistance genes to azole antimycotics) genes.

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

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

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

Pharmacokinetics:

The pharmacokinetics of fluconazole are similar for intravenous and oral use. After oral use, fluconazole is well absorbed, its plasma concentration (and total bioavailability) exceed 90% of those with intravenous use.

Simultaneous food intake does not affect the absorption of the drug taken orally. The concentration in blood plasma is proportional to the dose and reaches a maximum (cmax) in 0.5-1.5 hours after taking fluconazole on an empty stomach, and the 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 approaches 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 fluid, high concentrations are achieved that exceed serum levels.

Fluconazole accumulates in the stratum corneum. When taken at a dose of 50 mg once a day, the concentration of fluconazole after 12 days is 73 mcg/g, and 7 days after discontinuation of treatment – only 5.8 mcg/g. When used at a dose of 150 mg once a week, the concentration of fluconazole in the stratum corneum on day 7 is 23.4 mcg/g, and 7 days after taking the second dose -7.1 mcg/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 and 1.8 mcg/g in affected nails; 6 months after the end of therapy, fluconazole is still detected in the nails.

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

A long half-life from the blood plasma allows you to take fluconazole once for vaginal candidiasis.

Pharmacokinetics in elderly patients

It was found that a single use of fluconazole at a dose of 50 mg orally in elderly patients aged 65 years and older, some of which simultaneously took diuretics, With_max was achieved via 1,3 h after use and was 1.54 mcg/ml, the average values of AUC (area under the curve “concentration-time”) – 76,4 ± 20,3 µg×h/ml, and mean elimination half-life is – 46.2 h.

the values of these pharmacokinetic parameters above, than in younger patients, which probably related to reduced renal function characteristic of the elderly. Concomitant use of diuretics did not cause significant changes in AUC and_cmax.

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

Indications

Treatment of acute vaginal candidiasis when topical therapy is not applicable.

Use during pregnancy and lactation

Adequate and controlled studies of the use of fluconazole in pregnant women have not been conducted.

Currently, there is no evidence of the effect of low doses of fluconazole (150 mg once for the treatment of vulvovaginal candidiasis) on the increase in the frequency of adverse pregnancy outcomes, as well as the relationship with the occurrence of any specific malformations in the child.

When using high doses (400-800 mg/day) of fluconazole, several cases of multiple birth defects have been described in newborns whose mothers received fluconazole therapy for most or all of the first trimester.

The use of the drug in pregnant women is impractical, except for severe or life-threatening forms of fungal infections, if the intended benefit to the mother exceeds the possible risk to the fetus.

Women of childbearing age should use contraception.

Fluconazole is found in breast milk at the same concentration as in plasma, so its use during lactation is contraindicated.

Contraindications

• concomitant use of terfenadine (compared to the repeated use of fluconazole at a dose of 400 mg/day or more) (see section “Interaction with other medicines”);

• Hypersensitivity to fluconazole and other components of the drug or similar in the structure of the azole compounds;

• Children up to age 18;

• breast-feeding (see “pregnancy and breastfeeding”);

• Simultaneous use with drugs that increase the QT interval and are metabolized through CYP3A4 such as cisapride, astemizole, erythromycin, pimozide, quinidine and amiodarone (see section “Interaction with other medicines”);

• galactose Intolerance, lactase deficiency, glucose-galactose malabsorption.

With caution

* Impaired liver function;

* Concomitant use of potentially hepatotoxic drugs•

* Alcoholism•

* Proarrhythmogenic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance, concomitant use of drugs that cause arrhythmias);

• Impaired renal function;

• Rash associated with the use of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections•

* Concomitant use of terfenadine and fluconazole at a dose of less than 400 mg / day.

Side effects

The classification of adverse reactions by organ and system is presented with the frequency of their occurrence: very common (≥1/10); common (≥1/100, <1/10); infrequent (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare ( Drug tolerance is usually very good. The following adverse reactions have been reported in clinical and post-marketing studies (*) of fluconazole::

Nervous system disorders: often-headache; infrequently-dizziness*, convulsions*, taste changes*, paresthesia, insomnia, drowsiness; rarely-tremor.

Gastrointestinal disorders: often-abdominal pain, diarrhea, vomiting*, nausea; infrequently-flatulence, dyspepsia*, dry oral mucosa, constipation.

Disorders of the liver and biliary tract: often – increased serum activity of aminotransferases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), alkaline phosphatase; infrequently – jaundice*, cholestasis, increased bilirubin concentration; rarely – hepatotoxicity, in some cases fatal, impaired liver function*, hepatitis*, hepatocellular necrosis*, hepatocellular damage.

Skin and

subcutaneous fat disorders: often-rash; infrequently-pruritus, urticaria, increased sweating, drug rash; rarely-exfoliative skin lesions*, including Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis, facial edema, alopecia*.

Disorders of the blood and lymphatic system*: rarely-leukopenia, including neutropenia and agranulocytosis, thrombocytopenia, anemia.

Immune system disorders*: rarely-anaphylaxis (including angioedema, facial edema).

Disorders of the cardiovascular system*: rarely-an increase in the duration of the QT interval on the ECG, ventricular tachycardia of the “pirouette” type (see the section “Special instructions”).

Metabolic disorders*: rarely-increased plasma cholesterol and triglyceride concentrations, hypokalemia.

Musculoskeletal disorders: infrequently-myalgia.

Other: infrequently-weakness, asthenia, fatigue, fever, vertigo.

Some patients, especially those with serious diseases such as HIV infection or cancer, have experienced changes in blood parameters, kidney and liver function 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 get worse, or any other side effects that are not listed in the instructions are noted, you should immediately inform your doctor about this.

Interaction

Single or repeated use of fluconazole at a dose of 50 mg does not affect the metabolism of phenazone (Antipyrine) in a single dose.

Concomitant use of fluconazole with the following medications is contraindicated:

Cisapride. With the simultaneous use of fluconazole and cisapride, undesirable reactions from the heart are possible, including ventricular tachysystolic arrhythmia of the “pirouette” type (torsadedepointes). The use of fluconazole at a dose of 200 mg once a day and cisapride at a dose of 20 mg 4 times a day leads to a pronounced increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG.

Concomitant use of cisapride and fluconazole is contraindicated.

Terfenadine. When azole antifungal agents and terfenadine are used simultaneously, serious arrhythmias may occur as a result of an increase in the QT interval. When taking fluconazole at a dose of 200 mg / day, no increase in the QT interval was found.

However, the use of fluconazole at doses of 400 mg / day and above causes a significant increase in the concentration of terfenadine in blood plasma. Concomitant use of fluconazole at doses of 400 mg / day or more with terfenadine is contraindicated (see section “Contraindications”). Treatment with fluconazole at doses of less than 400 mg / day in combination with terfenadine should be carefully monitored.

Astemizole. Concomitant use of fluconazole with astemizole or other drugs that are metabolized by the cytochrome P450 system may be accompanied by an increase in serum concentrations of these drugs. Elevated plasma concentrations of astemizole can lead to prolongation of the QT interval and, in some cases, to the development of ventricular tachysystolic arrhythmia of the “pirouette” type (torsadedepointes). Concomitant use of astemizole and fluconazole is contraindicated.

Pimozide. Although no relevant invitro or invivo studies have been conducted, concomitant use of fluconazole and pimozide may lead to inhibition of pimozide metabolism.

In turn, an increase in plasma concentrations of pimozide can lead to prolongation of the QT interval and, in some cases, the development of ventricular tachysystolic arrhythmia of the “pirouette” type (torsadedepointes). Concomitant use of pimozide and fluconazole is contraindicated.

Quinidine. Although no relevant invitro or invivo studies have 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 ventricular tachysystolic arrhythmia of the “pirouette” type (torsadedepointes). Concomitant use of quinidine and fluconazole is contraindicated.

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

Amiodarone. Concomitant use of fluconazole and amiodarone may result in inhibition of amiodarone metabolism. The use of amiodarone was associated with prolongation of the QT interval. Concomitant use of fluconazole and amiodarone is contraindicated (see section “Contraindications”).

Caution should be exercised and possibly dose adjustments should be made when the following medications and fluconazole are used concomitantly::

Drugs that affect fluconazole:

Hydrochlorothiazide. Simultaneous repeated use of fluconazole and hydrochlorothiazide can lead to an increase in the concentration of fluconazole in blood plasma by 40%. The effect of this degree of severity does not require a change in the dosage regimen of fluconazole in patients receiving diuretics at the same time, but the doctor should take this into account.

Rifampicin. Combination with rifampicin resulted in a 25% decrease in AUC (area under the concentration-time curve) and a 20% shortening of the plasma half-life of fluconazole. Therefore, in patients receiving rifampicin concomitantly, it is necessary to consider the feasibility of increasing the dose of fluconazole.

Medications affected by fluconazole:

Fluconazole is a potent inhibitor of the cytochrome P450 isoenzyme CYP2C9 and CYP2C19 and a moderate inhibitor of the 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 taken concomitantly with fluconazole.

In this regard, caution should be exercised when using the following drugs simultaneously, and if such combinations are necessary, patients should be under close medical supervision. 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.

Alfentanyl. There is a decrease in clearance and volume of distribution, an increase in the half-life of alfentanil. This may be due to the inhibition of the CYP3A4 isoenzyme by fluconazole. You may need to adjust the dose of alfentanil.

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

Amphotericin B. In studies in mice (including those with immunosuppression), the following results were noted: a small additive antifungal effect in systemic infection caused by C. albicans, no interaction in intracranial infection caused by Cryptococcus Neoformans, and antagonism in systemic infection caused by A. fumigatus. The clinical significance of these results is not clear.

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

Possible development of bleeding (hematomas, bleeding from the nose and gastrointestinal tract, hematuria, melena). In patients receiving coumarin anticoagulants, it is necessary to constantly monitor the prothrombin time during therapy and for 8 days after simultaneous use. The feasibility of warfarin dose adjustment should also be evaluated.

Azithromycin. When concomitant oral use of fluconazole in a single dose of 800 mg with azithromycin in a single dose of 1200 mg, a pronounced pharmacokinetic interaction between both drugs was not established.

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

When a single dose of triazolam is administered concomitantly, fluconazole increases the AUC of triazolam by approximately 50%, with_{a max} of 25-50% and a half-life of 25-50% due to inhibition of triazolam metabolism. You may need to adjust the dose of triazolam.

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

Nevirapine. Concomitant use of fluconazole and nevirapine increases nevirapine exposure by approximately 100% compared to the control data for individual nevirapine use. Due to the risk of increased nevirapine release with concomitant use of medications, some precautions and careful monitoring of patients are necessary.

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

Cyclosporine. It is recommended to monitor the concentration of cyclosporine in the blood of patients receiving fluconazole, since in patients with a transplanted kidney, taking fluconazole at a dose of 200 mg / day leads to a slow increase in the concentration of cyclosporine in plasma. However, with repeated use of fluconazole at a dose of 100 mg / day, no changes in the concentration of cyclosporine in bone marrow recipients were observed.

Cyclophosphamide. When cyclophosphamide and fluconazole are co-administered, an increase in serum bilirubin and creatinine concentrations is noted. The combination of drugs is possible taking into account the risk of these disorders.

Fentanyl. One fatal outcome has been reported, possibly related to concomitant use of fentanyl and fluconazole. It is assumed that the violations are associated with fentanyl intoxication. Fluconazole has been shown to significantly extend the elimination time of fentanyl. It should be borne in mind that an increase in the concentration of fentanyl can lead to respiratory depression.

Halofantrine. Fluconazole may increase the concentration of halofantin in blood plasma due to inhibition of the CYP3A4 isoenzyme. When used concomitantly with fluconazole, as with other azole-type antifungal drugs, it is possible to develop ventricular tachysystolic arrhythmia of the “pirouette” type, so their combined use is not recommended.

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

It is necessary to monitor the concentration of creatinine kinase. If there is a significant increase in creatinine kinase concentration or if myopathy or rhabdomyolysis is diagnosed or suspected, therapy with MMC-CoA reductase inhibitors should be discontinued.

Losartan. 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 blood pressure monitoring is necessary.

Methadone. Fluconazole may increase the plasma concentration of methadone. You may need to adjust the dose of methadone.

Nonsteroidal anti-inflammatory drugs (NSAIDs). With_maxand AUC of flurbiprofen increased by 23% and 81%, respectively. Similarly, the_max and AUC of the pharmacologically active isomer [S-(+) – ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was co-administered with racemic ibuprofen (400 mg).

Concomitant use of fluconazole 200 mg / day and celecoxib 200 mg_{increased celecoxib cmax} and AUC by 68% and 134%, respectively. In this combination, it is possible to reduce the dose of celecoxib by half.

Despite the lack of targeted studies, fluconazole may increase the systemic exposure of other NSAIDs metabolized by the CYP2C9 isoenzyme (naproxen, lornoxicam, meloxicam, diclofenac). You may need to adjust the dose of NSAIDs.

When NSAIDs and fluconazole are used concomitantly, patients should be closely monitored to detect and control adverse events and toxicity associated with NSAIDs.

Oral contraceptives. Concomitant use of a combined oral contraceptive with fluconazole at a dose of 50 mg did not significantly affect hormone levels. When 200 mg of fluconazole is taken daily, the AUC of ethinyl estradiol and levonorgestrel increases by 40% and 24%, respectively. When taking 300 mg of fluconazole once a week, the AUC of ethinyl estradiol and norethindrone increase by 24% and 13%, respectively. Thus, repeated use of fluconazole at these doses is unlikely to affect the effectiveness of the combined oral contraceptive.

Phenytoin. Concomitant use of fluconazole and phenytoin may lead to an increase in the concentration of phenytoin in plasma to a clinically significant degree. Therefore, if the combined use of these drugs is necessary, it is necessary to monitor the concentration of phenytoin with dose adjustment in order to maintain the level of the drug within the therapeutic interval.

Prednisone. There is a report of acute adrenal insufficiency in a patient after liver transplantation against the background of discontinuation of fluconazole after a three-month course of therapy. Presumably, discontinuation of fluconazole therapy caused an increase in the activity of the CYP3A4 isoenzyme, which led to increased prednisone metabolism.

Patients receiving combination therapy with prednisone and fluconazole should be under close medical supervision when discontinuing fluconazole to assess the condition of the adrenal cortex.

Rifabutin. Concomitant use of fluconazole and rifabutin may lead to an increase in serum concentrations of the latter by up to 80%. Cases of uveitis have been reported with concomitant use of fluconazole and rifabutin. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored.

Saquinavir. The AUC increases by approximately 50%, and the_cmax increases by 55%. The clearance of saquinavir decreases by approximately 50% due to inhibition of hepatic metabolism of the CYP3A4 isoenzyme and P-glycoprotein. You may need to adjust the dose of saquinavir.

Sirolimus. An increase in the concentration of sirolimus in blood plasma is presumably due to inhibition of sirolimus metabolism through inhibition of the CYP3A4 isoenzyme and P-glycoprotein. This combination can be used with appropriate dose adjustment of sirolimus depending on the effect/concentration.

Preparations of sulfonylureas. Fluconazole increases the plasma half-life of oral hypoglycemic agents – sulfonylurea derivatives (chlorpropamide, glibenclamide, glipizide, tolbutamide). The combined use of fluconazole and oral hypoglycemic agents is allowed, but the doctor should keep in mind the possibility of hypoglycemia. Regular monitoring of blood glucose and, if necessary, dose adjustment of sulfonylureas is necessary.

Tacrolimus. The use of fluconazole and tacrolimus (orally) leads to a 5-fold increase in serum concentrations of the latter due to inhibition of tacrolimus metabolism occurring in the intestine by the CYP3A4 isoenzyme. No significant changes in the pharmacokinetics of drugs were observed with the use of tacrolimus intravenously. Cases of nephrotoxicity are described. Patients taking concomitant oral tacrolimus and fluconazole should be carefully monitored. The dose of tacrolimus should be adjusted depending on the degree of increase in its concentration in the blood.

Theophylline. When used concomitantly with fluconazole at a dose of 200 mg for 14 days, the average rate of plasma clearance of theophylline decreases by 18%. When prescribing fluconazole to patients taking theophylline in high doses, or patients with an increased risk of developing toxic effects of theophylline, you should monitor the appearance of symptoms of overdose of theophylline and, if necessary, adjust therapy accordingly.

Periwinkle alkaloid. Despite the lack of targeted studies, it is suggested that fluconazole may increase the concentration of periwinkle alkaloids (for example, vincristine and vinblastine) in blood plasma and, thus, lead to neurotoxicity, which may possibly be associated with inhibition of the CYP3A4 isoenzyme.

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

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

Voriconazole (inhibitor of the isoenzyme CYP2C9, CYP2C19 and CYP3A4). Concomitant use 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) leads to an increase in the concentration and AUC of voriconazole by 57% and 79%, respectively.

It has been shown that this effect persists with a decrease in the dose and / or frequency of taking any of the drugs. Concomitant use of voriconazole and fluconazole is not recommended.

Tofacitinib. Exposure to tofacitinib increases when it is co-administered with drugs that are both moderate inhibitors of the CYP3A4 isoenzyme and powerful inhibitors of the CYP2C19 isoenzyme (for example, fluconazole). You may need to adjust the dose of tofacitinib.

Ivacaftor. When used concomitantly with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) stimulator, ivacaftor exposure increased 3-fold and hydroxymethyl-ivacaftor (M1) exposure increased 1.9-fold. Patients taking concomitant CYP3A inhibitors such as fluconazole and erythromycin should reduce the dose of ivacaftor to 150 mg once daily.

Studies of the interaction of oral forms of fluconazole when administered concomitantly with food, cimetidine, antacids, as well as after total body irradiation to prepare for bone marrow transplantation have shown that these factors do not have a clinically significant effect on the absorption of fluconazole.

The listed interactions have been established with repeated use of fluconazole; drug interactions resulting from a single dose of fluconazole are not known.

Doctors should keep in mind that interactions with other drugs have not been specifically studied, but they are possible.

How to take, course of use and dosage

Inside. Capsules are swallowed whole.

In acute vaginal candidiasis, the drug is used once inside at a dose of 150 mg.

Use in the elderly

In elderly patients with no impaired renal function, the usual dosage regimen should be followed.

Use in patients with renal insufficiency

With a single dose, no dose change is required.

Overdose

Symptoms: hallucinations, paranoid behavior.

Treatment: symptomatic, gastric lavage, forced diuresis.

Hemodialysis for 3 hours reduces the plasma concentration by approximately 50%.

Special instructions

When using fluconazole 150 mg for vaginal candidiasis, patients should be warned that symptoms usually improve after 24 hours, but sometimes it takes several days for them to completely disappear. If symptoms persist for several days, you should consult a doctor.

In rare cases, the use of fluconazole was accompanied by toxic changes in the liver, including with a fatal outcome, mainly in patients with serious concomitant diseases.

In the case of hepatotoxic effects associated with fluconazole, there was no obvious dependence on the total daily dose, duration of therapy, gender and age of the patient. The hepatotoxic effect of fluconazole was usually reversible; signs of it disappeared after discontinuation of therapy.

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

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

During treatment with fluconazole, patients rarely developed exfoliative skin lesions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

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

If a rash appears in patients with invasive / systemic fungal infections, they should be carefully monitored and discontinue fluconazole if bullous changes or erythema multiforme occur.

Concomitant use of fluconazole at doses less than 400 mg / day and terfenadine should be carefully monitored (see section “Interaction with other medicinal products”).

Like other azoles, fluconazole can cause an increase in the QT interval on the ECG. When using fluconazole, an increase in the QT interval and ventricular fibrillation or flutter were observed very rarely in patients with severe diseases with multiple risk factors, such as organic heart disease, electrolyte disorders, and concomitant therapy that contributes to the development of such disorders. Therefore, in such patients with potentially proarrhythmic conditions, fluconazole should be used with caution.

Patients with liver, heart and kidney diseases should consult a doctor before using the drug.

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

Influence on the ability to drive vehicles and mechanisms

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

Form of production

Capsules

Storage conditions

Store at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Shelf

life is 3 years.

Active ingredient

Fluconazole

Conditions of release from pharmacies

By prescription

Dosage form

Capsules