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%.
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.
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 .Creatinine clearance (74 ml / min), the percentage of fluconazole excreted by the kidneys unchanged (0-24 h, 22%) and renal fluconazole clearance (0.124 ml / min / kg) in elderly patients are lower than in younger patients.
Pregnancy and lactation
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.Fluconazole is found in breast milk in the same concentration as in plasma, so its administration during lactation is contraindicated.
• 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.
• Violation of liver function indicators;
• Concomitant use of potentially hepatotoxic drugs;
• 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 simultaneous use of terfenadine and fluconazole in a dose of less than 400 mg / day.
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.If any of the side effects specified in the instructions are aggravated, or any other side effects not listed in the instructions are noted, you should immediately inform your doctor.
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 isoenzyme CYP3A4 and P-glycoprotein. This combination can be used with appropriate dose adjustment of sirolimus depending on the effect / concentration.
Sulfonylurea preparations. 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 developing hypoglycemia. Regular monitoring of blood glucose and, if necessary, dose adjustment of sulfonylurea preparations is necessary.
Tacrolimus. The use of fluconazole and tacrolimus (by mouth) leads to an increase in serum concentrations of the latter by a factor of 5 due to inhibition of the metabolism of tacrolimus, which occurs in the intestine through the CYP3A4 isoenzyme. Significant changes in the pharmacokinetics of drugs were not observed with the use of tacrolimus intravenously. Cases of nephrotoxicity are described. Patients simultaneously taking tacrolimus inward 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. With simultaneous use with fluconazole at a dose of 200 mg for 14 days, the average plasma clearance rate of theophylline decreases by 18%. When fluconazole is prescribed to patients taking theophylline in high doses or to patients with an increased risk of developing the toxic effects of theophylline, the symptoms of theophylline overdose should be monitored and, if necessary, adjust therapy accordingly.
Vinca alkaloid. Despite the lack of targeted studies, it is believed that fluconazole can increase the concentration of vinca alkaloids (e.g., vincristine and vinblastine) in blood plasma and, thus, lead to neurotoxicity, which may be associated with inhibition of the CYP3A4 isoenzyme.
Vitamin A. There is a report of one case of the development of adverse reactions from the central nervous system (CNS) in the form of a pseudotumor of the brain with the simultaneous use of completely transretinoic acid and fluconazole, which disappeared after the withdrawal of fluconazole. The use of this combination is possible, but you should remember about the possibility of undesirable reactions from the central nervous system.
Zidovudine. In patients receiving a combination of fluconazole and zidovudine, there is an increase in Cmax and AUC of zidovudine by 84% and 74%, respectively, 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 (the complex associated with AIDS) found a significant increase in the AUC of zidovudine (20%). Patients receiving this combination should be observed in order to identify side effects of zidovudine.
Voriconazole (an inhibitor of the isoenzyme CYP2C9, CYP2C19 and CYP3A4). The simultaneous use of voriconazole (400 mg 2 times a day on the first day, then 200 mg twice a day for 2.5 days) and fluconazole (400 mg on the first day, then 200 mg per day for 4 days) leads to an increase in the concentration and AUC of voriconazole by 57% and 79%, respectively.
It was shown that this effect persists with a decrease in the dose and / or frequency of taking any of the drugs. The simultaneous use of voriconazole and fluconazole is not recommended.
Tofacitinib. The exposure of tofacitinib increases when used together with drugs that are both moderate inhibitors of the CYP3A4 isoenzyme and potent inhibitors of the CYP2C19 isoenzyme (e.g., fluconazole). A dose adjustment of tofacitinib may be necessary.
Ivacaftor. When used simultaneously with ivacafluor, a stimulator of cystic fibrosis transmembrane conductivity regulator (CFTR), an increase in exposure of ivacafluor by 3 times and exposure of hydroxymethyl-ivacafluor (M1) by 1.9 times was observed. Patients taking CYP3A inhibitors at the same time, such as fluconazole and erythromycin, are recommended to reduce the dose of ivacafluor to 150 mg once a day.
Studies of the interaction of oral forms of fluconazole when it is taken with food, cimetidine, antacids, as well as after total body irradiation to prepare for bone marrow transplantation showed that these factors do not have a clinically significant effect on the absorption of fluconazole.
The listed interactions were established with repeated use of fluconazole; interactions with drugs resulting from a single dose of fluconazole are not known.Doctors should consider that the interaction with other drugs has not been specifically studied, but it is possible.
How to take, course of administration 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 in the absence of impaired renal function, the usual dosage regimen of the drug should be followed.
Use in patients with renal failureWith a single dose dose adjustment is not required.
Symptoms: hallucinations, paranoid behavior.
Treatment: symptomatic, gastric lavage, forced diuresis.
Hemodialysis within 3 hours reduces the plasma concentration by approximately 50%.
When using fluconazole 150 mg for vaginal candidiasis, patients should be warned that symptom improvement usually occurs after 24 hours, but sometimes it takes several days to completely disappear. If symptoms persist for several days, consult a doctor.
In rare cases, the use of fluconazole was accompanied by toxic changes in the liver, including fatal, 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; his signs disappeared after discontinuation of therapy.
Patients in whom liver dysfunction is observed during treatment with the drug should be monitored to detect signs of more serious liver damage. If there are clinical signs or symptoms of liver damage that may be associated with the use of fluconazole, the drug should be discontinued.
As with other azoles, fluconazole in rare cases can cause anaphylactic reactions.
During treatment with fluconazoloma, 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 drugs. In cases where a rash develops in patients with superficial fungal infection and is regarded as definitely associated with fluconazole, the drug should be discontinued.
When a rash appears in patients with invasive / systemic fungal infections, they should be carefully monitored and fluconazole should be discontinued if bullous changes or erythema multiforme occur.
The simultaneous use of fluconazole in doses of less than 400 mg / day and terfenadine should be carried out under close monitoring (see section "Interaction with other drugs").
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 was very rare in patients with severe diseases with multiple risk factors, such as organic heart disease, electrolyte imbalance, and concomitant therapy conducive to the development of such disorders. Therefore, in such patients with potentially proarrhythmic conditions, fluconazole should be used with caution.
Patients with diseases of the liver, heart and kidneys are advised to consult a doctor before using the drug.
Cases of superinfection caused by Candida strains other than Candidaalbicans, which often have natural resistance to fluconazole (e.g., Candidakrusei), have been reported. In such cases, alternative antifungal therapy may be required.
Impact on the ability to drive vehicles and mechanismsDue to the possibility of dizziness and other side effects associated with taking the drug during the treatment period, patients are advised to refrain from driving vehicles and engaging in other potentially dangerous activities that require an increased concentration of attention, speed of psychomotor and motor reactions.
Store at a temperature not exceeding 25 ° C.Keep out of the reach of children.