Flucostat, capsules

Active substance:

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;

hard gelatin capsules:

(for a dosage of 50 mg) case: titanium dioxide (E 171) - 3.0000%, iron oxide red (E 172) - 0.0857%, gelatin - up to 100%; cap: titanium dioxide (E 171) - 2.0000%, red iron oxide (E 172) - 0.7286%, gelatin - up to 100%;

(for a dosage of 150 mg) body and cap: titanium dioxide (E 171) - 2,0000%, gelatin - up to 100%.

Pharmacodynamics:

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

Fluconazole also demonstrated invitro activity in clinical trials for 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 internally, fluconazole is active on various models of fungal infections in animals. The activity of the drug with opportunistic mycoses, including those caused by Candidaspp, was demonstrated. (including generalized candidiasis in immunocompromised animals), Cryptococcus neoformans (including intracranial infections), Microsporumspp. and Trychophytonspp.

Fluconazole is highly specific for fungal enzymes dependent on cytochrome P450. Fluconazole therapy at a dose of 50 mg / day for up to 28 days does not affect the concentration of testosterone in blood plasma in men or the concentration of steroids in women of childbearing age.  

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

Mechanisms for the development of fluconazole resistance

Fluconazole resistance can develop in the following cases: a qualitative and quantitative change in the enzyme that is the target for fluconazole (lanosteril 14-α-demethylase), decreased access to the target fluconazole, or a combination of these mechanisms.

Point mutations in the ERG11 gene encoding a 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 a need for an increase in the concentration of fluconazole in the intracellular fluid to suppress all enzyme molecules in the cell.

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

These transporters include the main mediator encoded by the MDR (multidrug resistance) genes and the superfamily of the ATP-binding transporter cassette encoded by the CDR genes (Candida fungal resistance genes for azole antimycotics).

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

Candidaglabrata resistance is typically 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 μg / ml), it is recommended to use the maximum dose of fluconazole.

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

Pharmacokinetics:

The pharmacokinetics of fluconazole are similar when given intravenously and orally. After oral administration, fluconazole is well absorbed, its plasma concentration (and total bioavailability) exceed 90% of those with intravenous administration.  

Simultaneous food intake does not affect the absorption of the drug taken orally. The concentration in the blood plasma is proportional to the dose and reaches a maximum (C _max ) 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. Plasma protein binding is low (11-12%).

Fluconazole penetrates well into all body fluids. The concentration of the drug in saliva and sputum is similar to its plasma levels.

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

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 μg / g, and 7 days after discontinuation of treatment, only 5.8 μg / g. When applied at a dose of 150 mg once a week, the concentration of fluconazole in the stratum corneum on the 7th day is 23.4 μg / g, and 7 days after the second dose –7.1 μg / g.

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

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

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

Pharmacokinetics in elderly patients

It was found that with a single application of fluconazole at a dose of 50 mg orally in elderly patients aged 65 years and older, some of whom were simultaneously taking diuretics, C _{max was}  achieved 1.3 hours after administration and was 1.54 μg / ml, average AUC values ������(areas under the concentration-time curve) are 76.4 ± 20.3 μg × h / ml, and the average elimination half-life is 46.2 hours. 

The values ������of these pharmacokinetic parameters are higher than in young patients, which is probably due to the reduced renal function characteristic of the elderly. The simultaneous administration of diuretics did not cause a pronounced change in AUC and C _max .

Adequate and well-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 congenital malformations in newborns have been described, the mothers of which received fluconazole therapy for most or the entire first trimester.

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

Women of childbearing age should use contraception.

• Concomitant use of terfenadine (against the background of repeated administration of fluconazole at a dose of 400 mg / day or more) (see section "Interaction with other drugs");

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

• Children's age up to 18 years;

• Lactation period (see the section "Use during pregnancy and during breastfeeding");

• Concomitant use with drugs that increase the QT interval and are metabolized using the CYP3A4 isoenzyme, such as cisapride, astemizole, erythromycin, pimozide, quinidine and amiodarone (see the section "Interaction with other drugs");

• Galactose intolerance, lactase deficiency, glucose-galactose malabsorption.

Carefully

• Violation of liver function indicators;

• 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;

• The appearance of a rash during the use of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections;

The classification of adverse reactions by organs and systems is presented with an indication of the frequency of their occurrence: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000), including individual messages whose frequency is unknown (frequency cannot be estimated based on available data). Drug tolerance is usually very good. In clinical and post-marketing (*) studies of fluconazole, the following adverse reactions were noted:

Disorders from the nervous system: often - headache; infrequently - dizziness *, convulsions *, taste change *, paresthesia, insomnia, drowsiness; rarely - tremor.

Disorders from the gastrointestinal tract: often - abdominal pain, diarrhea, vomiting *, nausea; infrequently - flatulence, dyspepsia *, dry oral mucosa, constipation.

Violations 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 disorders and

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

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

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

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

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

Disorders from the musculoskeletal system: infrequently - myalgia.

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

In some patients, especially those with serious diseases such as HIV infection or cancer, changes in blood counts, kidney and liver functions were observed during treatment with fluconazole and similar drugs, however, the clinical significance of these changes and their relationship with treatment have not been established.

A single or multiple administration of fluconazole in a dose of 50 mg does not affect the metabolism of phenazone (Antipyrine) when they are taken once.

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

Cisapride. With the simultaneous use of fluconazole and cisapride, undesirable reactions from the heart are possible, including ventricular arrhythmias, tachysystolic type “pirouette” (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 marked increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG.

The simultaneous use of cisapride and fluconazole is contraindicated.

Terfenadine. With the simultaneous use of azole antifungal agents and terfenadine, serious arrhythmias may occur as a result of an increase in the QT interval. When taking fluconazole at a dose of 200 mg / day, an increase in the QT interval has not been established. 

However, the use of fluconazole in doses of 400 mg / day and above causes a significant increase in the concentration of terfenadine in blood plasma. The simultaneous 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 monitored closely.

Astemizole. The simultaneous use of fluconazole with astemizole or other drugs, the metabolism of which is carried out by the cytochrome P450 system, may be accompanied by an increase in serum concentrations of these agents. Elevated plasma concentrations of astemizole can lead to a prolonged QT interval and, in some cases, to the development of ventricular arrhythmias of the tachysystolic “pirouette” type (torsadedepointes). The simultaneous use of astemizole and fluconazole is contraindicated.

Pimozide. Despite the fact that no relevant studies have been conducted invitro or invivo, the simultaneous use of fluconazole and pimozide can lead to inhibition of pimozide metabolism. 

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

Quinidine. Despite the fact that no relevant studies have been conducted invitro or invivo, the simultaneous use of fluconazole and quinidine can also lead to inhibition of quinidine metabolism. The use of quinidine is associated with a prolongation of the QT interval and, in some cases, with the development of ventricular arrhythmias of the tachysystolic “pirouette” type (torsadedepointes). The simultaneous use of quinidine and fluconazole is contraindicated.

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

Amiodarone. The combined use of fluconazole and amiodarone can lead to inhibition of amiodarone metabolism. The use of amiodarone has been associated with a prolongation of the QT interval. The simultaneous use of fluconazole and amiodarone is contraindicated (see section "Contraindications").

Caution should be exercised and, possibly, dose adjusted while using the following drugs and fluconazole:

Drugs that affect fluconazole:

Hydrochlorothiazide. The 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 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 leads to a decrease in AUC (area under the concentration-time curve) by 25% and a shortening of the half-life of fluconazole from plasma by 20%. Therefore, in patients receiving rifampicin at the same time, it is necessary to consider the feasibility of increasing the dose of fluconazole.

Drugs affected by fluconazole:

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

In this regard, caution should be exercised while using the drugs listed below, and if necessary, such combinations should be under careful medical supervision. It should be borne in mind that the inhibitory effect of fluconazole persists for 4-5 days after discontinuation of the drug due to the long half-life.

Alfentanil. There is a decrease in clearance and volume of distribution, an increase in the half-life of alfentanil. Perhaps this is due to inhibition of the CYP3A4 isoenzyme by fluconazole. A dose adjustment of alfentanil may be required.

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

Amphotericin B. In studies in mice (including immunosuppression), the following results were noted: a slight additive antifungal effect in case of systemic infection caused by C. albicans, lack of interaction in intracranial infection caused by Cryptococcusneoformans and antagonism in systemic infection caused by A. fumigatus. The clinical significance of these results is not clear.

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

Perhaps the 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 adjusting the dose of warfarin should also be assessed.

Azithromycin With the simultaneous administration 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 has not been established.

Benzodiazepines (short acting). After ingestion of midazolam, fluconazole significantly increases the concentration of midazolam and psychomotor effects, and this effect is more pronounced after taking fluconazole inside than when it is administered intravenously. If concomitant benzodiazepine therapy is needed, patients taking fluconazole should be monitored to assess the feasibility of a corresponding dose reduction of benzodiazepine.

While taking a single dose of triazolam, fluconazole increases the AUC of triazolam by about 50%, C _max  by 25-50% and the half-life by 25-50% due to inhibition of the metabolism of triazolam. A dose adjustment of triazolam may be needed.

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

Nevirapine: Concurrent administration of fluconazole and nevirapine increases the exposure of nevirapine by approximately 100% compared with control data for a single use of nevirapine. Due to the risk of increased release of nevirapine with the concomitant use of drugs, 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. Recommended side effect control.

Cyclosporin. It is recommended to monitor the concentration of cyclosporine in the blood in 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 the plasma. However, with repeated administration of fluconazole at a dose of 100 mg / day, changes in the concentration of cyclosporin in bone marrow recipients were not observed.

Cyclophosphamide. With the simultaneous use of cyclophosphamide and fluconazole, an increase in serum concentrations of bilirubin and creatinine is noted. The combination of drugs is possible taking into account the risk of these violations.

Fentanyl. There is a report of one death, possibly associated with the simultaneous administration of fentanyl and fluconazole. Disorders are believed to be associated with fentanyl intoxication. Fluconazole has been shown to significantly lengthen fentanyl elimination time. It should be borne in mind that an increase in the concentration of fentanyl can lead to inhibition of respiratory function.

Halofantrine.Fluconazole may increase the concentration of halofantin in the blood plasma due to inhibition of the CYP3A4 isoenzyme. With simultaneous use with fluconazole, as well as with other azole-type antifungal drugs, ventricular arrhythmias of the tachysystolic pirouette type are possible, therefore, their combined use is not recommended.

GMK-CoA reductase inhibitors. With the simultaneous use of fluconazole with GMC-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme (such as atorvastatin and simvastatin) or the CYP2D6 isoenzyme (fluvastatin), the risk of myopathy and rhabdomyolysis increases. If simultaneous therapy with these drugs is necessary, patients should be observed in order to identify symptoms of myopathy and rhabdomyolysis. 

It is necessary to control the concentration of creatinine kinase. In the case of a significant increase in creatinine kinase concentration or if it is diagnosed or suspected of developing myopathy or rhabdomyolysis, 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 the antagonism of angiotensin-II receptors. Regular monitoring of blood pressure is required.

Methadone: Fluconazole may increase the plasma concentration of methadone. A dose adjustment of methadone may be needed.

Nonsteroidal anti-inflammatory drugs (NSAIDs). With _max and AUC of flurbiprofen increase by 23% and 81%, respectively. Similarly, C _max  and AUC of the pharmacologically active isomer [S - (+) - ibuprofen] increased by 15% and 82%, respectively, with the simultaneous use of fluconazole with racemic ibuprofen (400 mg).

With the simultaneous use of fluconazole at a dose of 200 mg / day and celecoxib at a dose of 200 mg, C _max  and AUC of celecoxib increase by 68% and 134%, respectively. In this combination, it is possible to halve the dose of celecoxib.

Despite the lack of targeted studies, fluconazole can increase the systemic exposure of other NSAIDs metabolized by the CYP2C9 isoenzyme (naproxen, lornoxicam, meloxicam, diclofenac). NSAID dosage adjustment may be needed.

With the simultaneous use of NSAIDs and fluconazole, patients should be under close medical supervision in order to identify and control adverse events and toxicities associated with NSAIDs.

Oral contraceptives. With the simultaneous use of a combined oral contraceptive with fluconazole in a dose of 50 mg, a significant effect on the level of hormones has not been established. With a daily intake of 200 mg of fluconazole AUC, ethinyl estradiol and levonorgestrel increase 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 in the indicated doses is unlikely to affect the effectiveness of the combined oral contraceptive.

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

Prednisone. There is a report on the development of acute adrenal cortex insufficiency in a patient after liver transplantation against the background of fluconazole withdrawal 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 an increased metabolism of prednisone.

Patients receiving combination therapy with prednisone and fluconazole should be under close medical supervision when taking fluconazole is canceled in order to assess the state of the adrenal cortex.

Rifabutin. The simultaneous use of fluconazole and rifabutin can lead to an increase in serum concentrations of the latter up to 80%. With the simultaneous use of fluconazole and rifabutin, cases of uveitis have been described. It is necessary to carefully observe patients simultaneously receiving rifabutin and fluconazole.

Saquinavir. AUC increases by approximately 50%, C _max  - by 55%. The clearance of saquinavir is reduced by approximately 50% due to inhibition of the hepatic metabolism of the isoenzyme CYP3A4 and P-glycoprotein. A dose adjustment of saquinavir may be needed.

Sirolimus. An increase in the concentration of sirolimus in blood plasma is presumably due to the inhibition of sirolimus metabolism through inhibition of the