Fluconazole-Teva, 50 mg capsules 7 pcs

Pharmacotherapeutic group: antifungal agent

ATX code: J02AC01

Pharmacological properties

Pharmacodynamics

Fluconazole is a synthetic antifungal drug (antimycotic) of the
triazole derivatives, whose mechanism of action is associated with selective inhibition of ergosterol biosynthesis, essential for the formation of the cell membrane of fungi.

It shows activity in vitro and in clinical infections against most of the following microorganisms: Candida albicans, Candida glabrata (strains moderately sensitive), Candida pararsilosis, Candida tropicalis, Cryptococcus neoformans.

Active in vitro against the following microorganisms, but the clinical significance of this effect is unknown: Candida dubliniensis, Candida guilliermodii, Candida kefyr, Candida lusitaniae.

In oral administration, fluconazole shows activity in various models of fungal infections in animals: in opportunistic mycoses, including those caused by Candida spp (including generalized candidiasis in immunocompromised animals); Cryptococcus neoformans (including intracranial infections); Microsporum spp.
and Trychoptyton spp. The activity of the drug was also established in models of endemic mycoses in animals, including infections caused by Blastomyces dermatitides, Coccidioides immitis (including intracranial infections), and Histoplasma capsulatum in animals
with normal and suppressed immunity.

Fluconazole has high specificity against fungal enzymes
dependent on cytochrome P-450. Fluconazole therapy at a dose of 50 mg/day for up to 28 days has no effect on plasma testosterone concentrations in men or on steroid hormone concentrations in women of childbearing age. Fluconazole at a dose of 200-400 mg/day has no clinically significant effect on endogenous steroid blood levels and their response to adrenocorticotropic hormone (ACTH) stimulation in healthy male volunteers.

Mechanisms for the development of resistance to fluconazole.

Resistance to fluconazole may develop in the following cases: a qualitative or quantitative change in the enzyme lanosterol 14-α-demethylase, which is a target for fluconazole, decreased access to this enzyme by 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 chemical compounds from the azole group
(including triazole derivatives, which include fluconazole). Increased
expression of the ERG11 gene leads to high concentrations of the target enzyme, which creates a need to increase 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 drugs from the fungal cell.
These transporters include a major mediator encoded by the MDR
(multidrug resistance) genes and a superfamily of ATP-binding transporters encoded by the CDR (Candida fungi resistance
genes to azole antimycotics) genes.

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

Resistance to Candida glabrata is usually mediated by CDR gene hyperexpression, which leads to resistance to many antimycotics from the azole group. For those strains of fungi for which the minimum inhibitory concentration (MIC) is defined as intermediate (16-32 µg/ml), maximum doses of
fluconazole are recommended.

Candida krusei should be considered resistant to fluconazole. The mechanism of
resistance is related to the reduced sensitivity of its target enzyme
to the inhibitory effects of fluconazole.

Pharmacokinetics

The pharmacokinetics of fluconazole when taken orally is similar to the pharmacokinetics of
intravenous (IV) administration.

Absorption. After oral administration fluconazole is well absorbed, its concentration
in blood plasma (and overall bioavailability) exceeds 90% of the concentration of fluconazole
in blood plasma after intravenous administration. Simultaneous intake of food does not affect absorption of the drug when administered orally. Maximal concentration (C_max) is reached in
0.5-1.5 hours after fluconazole administration on an empty stomach. The plasma concentration is proportional to the dose. If the recommended daily dose is taken once daily, the equilibrium concentration (C_ss) reaches 90% by the 4th-5th day of treatment with the drug. Administering a shock dose of 2 times the average daily dose on day 1 accelerates the attainment of 90% C_ss by day 2.

Dispensing. The amount of distribution approaches the total water content of the body. Binding to blood proteins is relatively low (11-12%).

Fluconazole penetrates well into many body fluids. Fluconazole concentrations in saliva, sputum, breast milk, joint fluid and peritoneal fluid are similar to its concentration in blood plasma. Constant values of concentration of the drug in vaginal secretion are reached after 8 hours after oral administration and are maintained at this level for at least 24 hours. In patients with fungal meningitis the concentration of fluconazole in cerebrospinal fluid is about 80% of its concentration in blood plasma. In the stratum corneum of the epidermis, epidermis-dermis and sweat fluid high concentrations of the drug are achieved that exceed serum concentrations. Fluconazole accumulates in the stratum corneum of the epidermis. When administered in a dose of 50 mg once daily, fluconazole concentration in this layer of skin after 12 days was 73 mcg/g, and after 7 days after discontinuation of treatment –
5.8 mcg/g. When used in a dose of 150 mg once a week, the concentration of fluconazole in the stratum corneum was 23.4 µg/g on day 7, and
7.1 µg/g 7 days after the second dose. The concentration of fluconazole in the nail plates after 4 months of use at a dose of 150 mg once/week was 4.05 µg/g in healthy nails and 1.8 µg/g in affected nails; 6 months after completion of therapy, fluconazole was still detected in the nail plates.

Metabolism and excretion. Fluconazole is excreted mainly by the kidneys; approximately 80% of the administered dose is found unchanged in the urine. Fluconazole clearance
is proportional to creatinine clearance. No drug metabolites were detected in blood. The long elimination half-life (T_½) from plasma allows fluconazole
to be taken once for vaginal candidiasis and once daily or once/week for other indications.

Pharmacokinetics in selected patient groups

Pharmacokinetics in women during breastfeeding

. A pharmacokinetics study involving 10 women who temporarily or completely stopped breastfeeding assessed plasma and breast milk concentrations of fluconazole for 48 hours after a single dose of 150 mg of fluconazole.
Fluconazole was detected in breast milk at a mean concentration of
approximately 98% of the maternal plasma fluconazole concentration. The mean peak concentration was 2.61 mg/L after 5.2 hours of drug administration.

Pharmacokinetics in children

The following pharmacokinetic values were obtained in children:

u>Pharmacokinetics in elderly patients

It was found that with a single oral dose of 50 mg of fluconazole
in elderly patients aged 65 years or older, some of whom were simultaneously taking diuretics, C_max was reached 1.3 hours after ingestion and was 1.54 mcg/mL, mean AUC values were 76.4 ± 20.3 mcg-h/mL, and mean half-life was 46.2 hours. 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.

The creatinine clearance (74 mL/min), the percentage of fluconazole excreted by the kidneys
unchanged (0-24 hours, 22%) and the renal clearance of fluconazole (0.124 mL/min/kg) are lower in elderly patients compared with younger patients.

Indications

Active ingredient

Composition

One capsule contains: the active ingredient fluconazole 50.00 mg, 100.00 mg or 150.00 mg; auxiliary substances: 47.00/94.00/141.00 mg lactose monohydrate,
corn starch 16.65/33.30/49.95 mg, colloidal anhydrous silica 0.1125/0.225/0.3375 mg, sodium lauryl sulfate 0.1125/0.225/0.3375 mg, magnesium stearate 1.125/2.25/3.375 mg.

Jelatin capsule: casing: titanium dioxide (E171) 0.46/0.73/0.91 mg, FCF diamond blue dye (E133) -/-/0.015 mg, gelatin q.s. to 22.8/q.s. Up to 36.6/q.s. up to 45.6 mg; cap: titanium dioxide (E171) 0.30/0.73/0.61 mg, FCF diamond blue dye (E133) 0.005/0.056/0.010 mg, gelatin q.s. to 15.2/q.s. to 24.4/q.s. to 30.4 mg.

How to take, the dosage

Interaction

Single or multiple administration of fluconazole at a dose of 50 mg does not affect the metabolism of fenazone (Antipyrine) when they are used simultaneously.

Simultaneous use of fluconazole with the following drugs
is contraindicated:

Cisapride: concomitant use of fluconazole and cisapride may cause adverse cardiac reactions, including.including ventricular fibrillation/tripping (torsade de ruintees). Fluconazole administration at a dose of 200 mg once daily and cisapride at a dose of 20 mg
4 times daily leads to a marked increase in plasma concentrations of cisapride and prolongation of QT interval on ECG. Simultaneous administration of cisapride and fluconazole is contraindicated.

Terfenadine: Concomitant use of azole antifungal agents and terfenadine may cause serious arrhythmias as a result of an increased QT interval. No increase in QT interval has been found in fluconazole administration at a dose of 200 mg/day, but use of fluconazole at doses of 400 mg/day and higher causes a 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 plasma concentrations of astemizole may lead to prolongation of the QT interval and, in some cases, to the development of pirouette-type ventricular tachycardia (torsade de pointes). Simultaneous use of astemizole and fluconazole is contraindicated.

Pimozide: Although there have been no relevant studies invitro or in vivo, concomitant use of fluconazole and pimozide may result in inhibition of pimozide metabolism. In turn, increased plasma concentrations of pimozide may cause prolongation of the QT interval and, in some cases, the development of pirouette-type ventricular tachycardia (torsade de pointes). Simultaneous use of pimozide and fluconazole is contraindicated.

Hinidine: Although there have been no relevant studies invitro or in vivo, simultaneous use of fluconazole and quinidine may result in inhibition of quinidine metabolism. In turn, an increase in plasma concentrations of quinidine may lead to prolongation of the QT interval and, in some cases, to the development of pirouette-type ventricular tachycardia (toisade de pointes). Simultaneous use of quinidine and fluconazole is contraindicated.

Eritromycin: Concomitant use of fluconazole and erythromycin potentially leads to an increased risk of cardiotoxicity (QT interval prolongation, pirouette-type ventricular tachycardia (torsade de pointes) and, consequently, sudden cardiac arrest. Simultaneous use of fluconazole and erythromycin is contraindicated.

The following drugs are not recommended:

Halofantrine: fluconazole may increase plasma
halofantrine concentrations due to inhibition of the CYP3A4 isoenzyme. Concomitant use of fluconazole and halofantrine may increase the risk of cardiotoxicity (QT interval prolongation, “torsade de pointes”) and, therefore, sudden cardiac arrest. Simultaneous use of fluconazole and halofantrine is not recommended.

Caution should be exercised when using fluconazole concomitantly:

Amiodarone:use of amiodarone has been associated with QT interval prolongation.
Caution should be exercised when using fluconazole and
amiodarone concomitantly, especially when taking a high dose of fluconazole (800 mg).

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

Drugs that affect the metabolism and effects of fluconazole:

Hydrochlorothiazide: Repeated use of hydrochlorothiazide simultaneously with fluconazole results in a 40% increase in plasma fluconazole concentration. This degree of effect does not require a change in fluconazole dosing regimen
in patients receiving concomitant diuretics, but the physician should consider this.

Rifampicin: Concomitant use of fluconazole and rifampicin leads
to a 25% decrease in AUC and a 20% decrease in the half-life of fluconazole.
In patients concomitantly taking rifampicin, it is necessary to consider the advisability of increasing the dose of fluconazole.

Drugs affected by fluconazole:

Fluconazole is a moderate inhibitor of the CYP3A4 and CYP2C9
cytochrome P450 isoenzymes. Fluconazole is also an inhibitor of CYP2C19 isoenzymes. In addition, 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 concomitant use of these drugs, 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 drug withdrawal due to the long elimination half-life.

Alfentanil: There is a decrease in clearance and volume of distribution and an increase in the half-life of alfentanil. This may be due to inhibition of CYPCA4 isoenzyme by fluconazole. Adjustment of the dose of alfentanil may be necessary.

Amitriptyline, nortriptyline: increased 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 initiation. The dose of amitriptyline/nortriptyline should be adjusted if necessary.

Amphotericin B: The following results have been reported in studies in mice (including immunosuppressed mice): A small additive antifungal effect in systemic infection caused by Candida albicans, no interaction in intracranial infection caused by Cryptococcus neoformans and antagonism in systemic infection caused by Aspergillus fumigatus. The clinical significance of these results
is unclear.

Anticoagulants: like other antifungal agents from the group of azole derivatives, fluconazole when used simultaneously with warfarin increases prothrombin time (by 12%), due to which the development of bleeding (hematomas, bleeding from the nose and gastrointestinal tract, hematuria, melena) is possible. In patients receiving coumarin or indanedio anticoagulants and fluconazole, prothrombin time should be constantly monitored during the therapy and for 8 days after cessation of concomitant use. The appropriateness of anticoagulant dose adjustment should also be evaluated.

Azithromycin: No significant pharmacokinetic interaction between the two drugs was found in concomitant oral use of fluconazole in a single dose of 800 mg with azithromycin in a single dose of 1200 mg.

Benzodiazepines(short-acting): After oral administration of midazolam, fluconazole
significantly increases midazolam concentrations and psychomotor effects, and this effect is more pronounced after oral fluconazole than when it is administered intravenously. If concomitant therapy with benzodiazepines is necessary, patients taking fluconazole should be monitored to reduce the benzodiazepine dose accordingly. When a single dose of triazolam is taken concomitantly, fluconazole increases the AUC of triazolam by approximately 50%, Cmax by 25-32% and T1/2 by 25-50% through inhibition of triazolam metabolism. Dose adjustment
of triazolam may be necessary.

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

Nevirapine: Combined administration of fluconazole and nevirapine increases exposure to nevirapine by approximately 100% compared to 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 the CYP3A4 isoenzyme. Fluconazole increases systemic exposure to calcium channel antagonists. It is recommended to control the development of side effects.

Cyclosporine: In patients with a transplanted kidney, the use of fluconazole at a dose of 200 mg/day leads to a slow increase in the concentration of cyclosporine. However, no changes in cyclosporine concentrations were observed in bone marrow recipients when fluconazole was administered repeatedly at a dose of 100 mg/day. When concomitant use of fluconazole and cyclosporine it is recommended to monitor the concentration of cyclosporine in blood.

Cyclophosphamide: When concomitant use of cyclophosphamide and fluconazole, increased serum concentrations of bilirubin and creatinine are observed. This combination is acceptable given the risk of increased bilirubin and creatinine concentrations.

Fentanyl: One fatality has been reported, possibly related to the simultaneous administration of fentanyl and fluconazole. The disorders 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 depressed respiratory function.

HMG-CoA reductase inhibitors: Conazole concomitant use with HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme (such as atorvastatin and simvastatin) or CYP2D6 isoenzyme (such as fluvastatin) increases the risk of myopathy and rhabdomyolysis. If concomitant therapy with these drugs is necessary, patients should be monitored to detect 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 HMG-CoA reductase inhibitors should be discontinued.

Lozartan: Fluconazole inhibits the metabolism of losartan to its active metabolite
(E-3174), which is responsible for most of the effects associated with angiotensin II receptor antagonism. Regular blood pressure control is necessary.

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

Non-steroidal anti-inflammatory drugs (NSAIDs):The Cmax and AUC of flurbiprofen are increased by 23% and 81%, respectively. Similarly, the Cmax 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).

When fluconazole at a dose of 200 mg/day and celecoxib at a dose of
200 mg, the Cmax and AUC of celecoxib increased 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 the CYP2C9 isoenzyme (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Dose adjustment of NSAIDs may be necessary.

In concomitant use of NSAIDs and fluconazole, patients should be closely monitored medically to detect and control adverse events and manifestations of toxicity associated with NSAIDs.

Olaparib: moderate CYP3A4 isoenzyme inhibitors, such as fluconazole,
increase the plasma concentration of olaparib. Their simultaneous use is not recommended. If concomitant use cannot be avoided, the
dose of olaparib should be reduced to 200 mg twice daily.

Peroral contraceptives: no significant effect on hormone levels was found with concomitant use of the combined oral contraceptive with fluconazole at a dose of 50 mg, whereas daily administration of 200 mg of fluconazole increased the AUC of ethinylestradiol and levonorgestrel by 40 % and 24 % respectively,
and the AUCs of ethinylestradiol and norethindrone increase by 24% and 13%, respectively, when taking 300 mg of fluconazole once a week. Thus, repeated use of fluconazole at these doses is unlikely to affect the efficacy of the
combined oral contraceptive.

Phenytoin:Combined use of fluconazole and phenytoin may be accompanied by clinically significant increases in phenytoin concentrations. If concomitant use of both drugs is necessary, phenytoin concentrations should be monitored and the dose should be adjusted accordingly to ensure therapeutic serum concentrations.

Prednisone:There has been a report of acute adrenal insufficiency in a patient after liver transplantation on reversal of fluconazole after three months of therapy. Presumably, discontinuation of fluconazole therapy caused increased CYP3A4 isoenzyme activity, which led to increased metabolism of
prednisone.

Patients receiving combined therapy with prednisone and fluconazole
should be closely monitored medically when discontinuing
fluconazole to assess the adrenal cortex.

Rifabutin:The concomitant use of fluconazole and rifabutin may result in increased serum concentrations of the latter up to 80%. Cases of uveitis have been described with concomitant use of fluconazole and rifabutin. Patients receiving rifabutin and fluconazole concomitantly
should be closely monitored.

Sauvinavir: AUC is increased by approximately 50%, Cmax is increased by 55%, and saquinavir clearance is decreased by approximately 50% due to inhibition of hepatic
metabolism of CYP3A4 isoenzyme and inhibition of P-glycoprotein. The dose of saquinavir may
need to be adjusted.

Syrolimus:increased plasma concentrations of sirolimus, 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.

Sulfonylurea derivatives: fluconazole, when taken concomitantly with sulfonylurea derivatives, results in an increased half-life of oral sulfonylurea drugs (chlorpropamide, glibenclamide, glipizide, and tolbutamide). People with diabetes may be treated with fluconazole combined with oral sulfonylureas, but
the possibility of hypoglycemia should be considered, and regular monitoring of blood glucose and, if necessary, dosage adjustment of sulfonylureas should be performed.

Tacrolimus: concomitant use of fluconazole and tacrolimus (oral) results
in a 5-fold increase in serum concentrations of the latter due to inhibition
of tacrolimus metabolism occurring in the gut via the CYP3A4 isoenzyme. No significant changes in pharmacokinetics of the drugs were noted when using tacrolimus intravenously. Cases of nephrotoxicity have been described. Patients receiving 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: When used concomitantly with fluconazole at a dose of 200 mg for
14 days, the average plasma clearance rate of theophylline is reduced by 18%.
If fluconazole is administered to patients taking high doses of theophylline or to patients with increased risk of theophylline toxicity, the appearance of symptoms of theophylline overdose should be observed and the therapy should be adjusted accordingly, if necessary.

Tofacitinib:The exposure of tofacitinib is increased when it is co-administered with drugs that are both moderate inhibitors of the CYP3A4 and CYP2C19 isoenzymes (e.g., fluconazole). It may be necessary to adjust the dose of tofacitinib.

Alkaloid of periwinkle: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 possibly be due to inhibition of the CYP3A4 isoenzyme.

Vitamin A:there has been one reported case of adverse central nervous system (CNS) reactions in the form of pseudotumor cerebri when using all-trans retinoic acid and fluconazole concomitantly, which disappeared after fluconazole was withdrawn. The use of this combination is possible, but the possibility of adverse CNS reactions should be kept in mind.

Zidovudine: concomitant use with fluconazole showed an 84% and 74% increase in Cmax and AUC of zidovudine, respectively. This effect is probably due to 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 in patients with AIDS and ARC (AIDS-related complex) a significant increase in AUC
zidovudine (20%) was found. Patients receiving this combination should be monitored for side effects of zidovudine.

Voriconazole (CYP2C9, CYP2C19 and CYP3A4 isoenzyme inhibitor): 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) resulted in a 57 % and 79 % increase in voriconazole concentration and AUC, respectively. This effect has been shown to persist with dose reduction and/or reduction in the frequency of administration of either drug. Simultaneous use of voriconazole and fluconazole is not recommended.

Ivacaftor: concomitant use with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) stimulator, resulted in a 3-fold increase in ivacaftor exposure and a 1.9-fold increase in hydroxymethyl ivacaftor (M1) exposure. In patients concomitantly taking moderate CYP3A inhibitors, such as fluconazole and erythromycin, it is recommended to reduce the dose of ivacaftor to 150 mg once
per day.

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 when fluconazole is used repeatedly; no drug-drug interactions are known as a result of single fluconazole administration.

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

Special Instructions

Superinfections caused by strains of Candida albicans
other than Candida have been reported./em>, which often have natural resistance to fluconazole (e.g., Candida krusei). In such cases, alternative antifungal therapy may be necessary.

In pregnancy, fluconazole should be avoided except in cases of severe and potentially life-threatening fungal infections, when the expected benefit to the mother exceeds the possible risk to the fetus.

Effective contraception in women of childbearing age should be considered for the duration of treatment and for approximately one week (5-6 half-lives) after the last dose of the drug (see “Use in pregnancy and breastfeeding”).

In rare cases the use of fluconazole has been accompanied by toxic liver changes, including fatal, mainly in patients with serious
comorbidities. In the case of hepatotoxic effects associated
with the use of fluconazole, no clear dependence on the total daily dose of the drug, the duration of therapy, sex and age of the patient was noted. Hepatotoxic effects of the drug were usually reversible; signs of them disappeared after discontinuation of therapy. Patients in whom liver function parameters are disturbed during treatment with the drug should be observed in order to detect 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 have rarely developed exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. AIDS patients are more prone to develop severe skin reactions when using many drugs. If a patient develops a superficial fungal infection rash during treatment, which can be associated with fluconazole use, the drug should be discontinued. If rash appears in patients with invasive/systemic fungal infections, they should be closely monitored and the drug should be withdrawn if bullous lesions or erythema multiforme appear.

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

Like other azoles, fluconazole may cause QT interval prolongation on ECG.
Fluconazole causes prolongation of the QT interval by inhibiting potassium channel current of internal rectification. The QT interval prolongation caused by other drugs (such as amiodarone) may be enhanced by inhibitors of cytochrome Р450 isoenzyme 3A4 (CYP) (see section “Interaction with other medicinal products”). When using fluconazole, QT interval prolongation and ventricular fibrillation/rattling 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. An increased risk of developing life-threatening
ventricular arrhythmias and polymorphic ventricular tachycardia may occur in patients with hypokalemia and advanced heart failure. Therefore, these patients with potentially proarrhythmic conditions should use fluconazole with caution.

Patients with liver, heart and kidney diseases are recommended to consult a physician before using the drug
. When using fluconazole 150 mg
for vaginal candidiasis, patients should be warned that improvement in symptoms is usually seen in 24 hours, but it sometimes takes several days for symptoms to disappear
completely. If symptoms persist for several days, a doctor should be consulted.

The evidence for the effectiveness of fluconazole in treating other types of endemic
mycoses such as paracoccidioidomycosis, sporotrichosis, and histoplasmosis is limited, making it impossible to determine specific dosing recommendations. Fluconazole is a moderate inhibitor of the CYP2C9 isoenzyme and a moderate inhibitor of the CYP3A4 isoenzyme. Fluconazole is also an inhibitor of CYP2C19 isoenzyme. Caution is recommended during concomitant therapy with medicinal products with narrow therapeutic profile
metabolized by CYP2C9, CYP2C19 and CYP3A4 isoenzymes (see section “Interaction with other medicinal products”).

The development of adrenal cortical insufficiency has been reported in patients receiving therapy with other azoles (e.g., ketoconazole). Reversible cases of adrenal insufficiency have been observed in patients receiving
fluconazole.

Influence on the ability to drive and operate vehicles

When using the drug, the possibility of dizziness and seizures should be taken into account.

Synopsis

Contraindications

With caution

Side effects

The incidence of adverse reactions is rated as follows: very common (≥1/10), common (≥1/100 to ˂1/10), infrequent (≥1/1000 to ˂1/100), rare (≥1/10000 to ˂1/1000), very rare (˂1/10 000), frequency unknown (data not available to estimate).

The tolerability of the drug is usually good.

The following adverse reactions have been reported in clinical and post-marketing (*) studies of fluconazole:

Nervous system adverse reactions: often – headache; frequently – dizziness*, seizures*, change in taste*, paresthesia, insomnia, somnolence; rarely – tremor.

The digestive system: often – abdominal pain, diarrhea, nausea, vomiting*; frequently – meteorism, dyspepsia*, dry mucous membrane of the mouth, constipation.

Hepatobiliary system disorders: often – increased serum aminotransferase activity (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), alkaline phosphatase; frequently – cholestasis, jaundice*, increased concentration of bilirubin; rarely – hepatotoxicity, in some cases with lethal outcome, impaired liver function*, hepatitis*, hepatocellular necrosis*, hepatocellular damage.

Skin side: Frequent – rash; frequent – cutaneous itching, urticaria, increased sweating, drug rash (including persistent drug rash);
frequent – exfoliative skin lesions*, including Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis, facial edema, alopecia*, frequency unknown – drug rash with eosinophilia and
systemic manifestations (DRESS syndrome).

Hematopoietic and lymphatic system disorders*: rare – leukopenia, including neutropenia and agranulocytosis, thrombocytopenia, anemia.

On the immune system*: anaphylaxis (including angioedema).

Cardiovascular system disorders*: rarely – increased QT interval on ECG, pirouette-type ventricular tachycardia (torsade de pointes) (see section “Special Indications”).

Metabolism disorders*: rarely – increased concentrations of cholesterol and triglycerides in plasma, hypokalemia.

Musculoskeletal system disorders: infrequent – myalgia.

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

In some patients, especially those with serious illnesses, such as AIDS or cancer, during treatment with Fluconazole-Teva and similar drugs changes in blood parameters, renal and hepatic function have been observed (see section “Special indications”), but the clinical significance of these changes and their relation to the treatment are not determined.

Overdose

Pregnancy use

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

In pregnancy, fluconazole should be avoided except in cases of severe and potentially life-threatening fungal infections, when the expected benefit to the mother exceeds the possible risk to the fetus.

Effective contraceptive methods should be considered in women of childbearing
age for the duration of treatment and for approximately one week
(5-6 half-lives) after the last dose of the drug (see Pharmacokinetics section).

There have been reported cases of spontaneous abortion and congenital abnormalities
in infants whose mothers were treated with fluconazole at a dose of 150 mg once
or repeatedly in the first trimester of pregnancy. There have been cases of multiple
birth defects in newborns whose mothers were treated with fluconazole at a high dose
(400-800 mg/day) for most or all of the first trimester. The following developmental abnormalities have been noted: brachycephaly, facial abnormalities, skull vault abnormalities,
wolf’s mouth, curvature of the femurs, thinning and elongation of the ribs, arthrogryposis, and congenital heart defects.

Fluconazole is detected in breast milk at concentrations close to plasma levels (see section on Pharmacokinetics). The half-life of the drug from breast milk is approximately equal to that of plasma – 30 hours. Estimated fluconazole dose absorbed by infant (taking into account that the average amount of milk consumed is 150 ml/kg daily) and calculated according to the average peak concentration of the drug in breast milk is 0.39 mg/kg/day, which is approximately equal to 40% of the recommended neonatal dose (for children younger than 2 weeks) or 13% of the recommended infant dose in the treatment of candidiasis mucosa.

Breastfeeding may be continued after a single dose of fluconazole
of 150 mg. Breastfeeding is not recommended after multiple doses or after taking
a high dose of fluconazole. When deciding whether to prescribe Fluconazole-Teva during breastfeeding, the following
factors should be considered: the benefits of breastfeeding for the health and development of the infant in conjunction with the clinical indications for prescribing Fluconazole-Teva and the potential for any potential side effects in the infant or the impact of the mother’s comorbidities on the health of the infant.

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