Fluconazole STADA - instructions for use, dose, side effects, contraindications

auxiliary substances: lactose monohydrate 0.2 mg, potato starch 28.7 mg, croscarmellose sodium 11.7 mg, povidone (low molecular weight polyvinylpyrrolidone) 8.0 mg, magnesium stearate -1.1 mg, talc - 0.2 mg; capsules hard gelatinous No. 1: gelatin (97.7426%), titanium dioxide (1.3333%), quinoline yellow color [E 104] (0.9197%),dye sunset sunset yellow [E 110] (0.0044%).

Description:

Hard gelatin capsules number 1, the body is yellow, the lid is yellow. The contents of the capsules are a granular powder of white or white with a yellowish hue. Conglomerates are allowed, which when pressed with a glass rod are easily converted into a powder.

Pharmacotherapeutic group:Antifungal agent.

ATX: & nbsp

J.02.A.C Triazole derivatives

J.02.A.C.01 Fluconazole

Pharmacodynamics:

Antifungal agent, has a highly specific effect, inhibiting the activity of enzymes of fungi, dependent on cytochrome P450. It blocks the transformation of lanosterol of fungal cells into membrane lipid-ergosterol; increases the permeability of the cell membrane, disrupts its growth and replication.

Fluconazole, being highly selective for cytochrome P450 fungi, practically does not inhibit these enzymes in the human body (in comparison with itraconazole, clotrimazole, econazole and ketoconazole less inhibits oxidative processes dependent on cytochrome P450 in human liver microsomes). Does not have anti-androgenic activity.

Active with opportunistic fungal infections, incl. caused by Candida spp. (including generalized forms of candidiasis on the background of immunodepression), Cryptococcus neoformans and Coccidioides immitis (including intracranial infections), Microsporum spp. and Trichophyton spp .; with endemic mycoses caused by Blastomyces dermatidis, Histoplasma capsulatum (including with immunodepression).

Mechanisms of development of resistance to fluconazole

Resistance to fluconazole may develop in the following cases: a qualitative or quantitative change in the enzyme that is the target for fluconazole (lanosterol 14-a-demethylase), a decrease in access to the target of fluconazole, or a combination of these mechanisms.

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

The second significant mechanism of resistance is the active removal of fluconazole from the intracellular space by activating the two types of transporter involved in the active excretion of drugs from the fungal cell.These transports include the main mediator, encoded by MDR (multidrug resistance) genes, and the superfamily of the transport ATP-binding cassette encoded by CDR genes (Candida fungal resistance genes to azole antimycotics). The overexpression 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 the 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 an intermediate (16-32 μg / ml), it is recommended to apply the maximum doses of fluconazole.

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

Pharmacokinetics:

After oral administration fluconazole it is well absorbed, its bioavailability is 90%. The maximum concentration (Cmax) after ingestion of 150 mg of the drug on an empty stomach is 90% of the plasma concentration with intravenous administration at a dose of 2.5-3.5 mg / l. Simultaneous food intake does not affect the absorption of fluconazole ingested.

Time to reach the maximum concentration after ingestion on an empty stomach 150 mg of the drug - 0.5 - 1.5 hours. The concentration in the plasma is in direct proportion to the dose. 90% of the equilibrium concentration is reached by the 4th-5th day of treatment with the drug (when taken 1 time / day). The introduction of the "shock" dose (on the first day), which is 2 times higher than the usual daily dose, allows reaching a concentration corresponding to 90% of the equilibrium concentration by the second day. The volume of distribution approximates the total water content in the body. The connection with blood plasma proteins is 11-12%. Fluconazole well penetrates into all body fluids. The concentration of the active substance in breast milk, articular fluid, saliva, sputum and peritoneal fluid is similar to that in plasma. Constant values in the vaginal secretion are reached 8 hours after ingestion and are held at this level for at least 24 hours. Fluconazole well penetrates into the cerebrospinal fluid (CSF), with fungal meningitis, the concentration in the CSF is about 80% of its concentration in the plasma. In the fluid, epidermis and horny layer of the skin (selective accumulation), concentrations exceeding the serum levels are achieved.On day 7 after ingestion of 150 mg of fluconazole, its concentration in the stratum corneum is 23.4 μg / g, 1 week after the second dose, 7.1 μg / g. The concentration of fluconazole in healthy nails after 4 months of use at a dose of 150 mg once a week is 4.05 μg / g and 1.8 μg / g - in the affected nails.

It is an inhibitor of the isoenzyme CYP2C9 in the liver. Metabolites of fluconazole in peripheral blood were not detected.

It is excreted mainly by the kidneys (80% - unchanged, 11% - in the form of metabolites). T1 / 2 (half-life) fluconazole - about 30 hours. The clearance of fluconazole is proportional to the creatinine clearance (CC). After hemodialysis for 3 hours the concentration of fluconazole in plasma is reduced by 50%.

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 concurrently took diuretics, Cmax was achieved 1.3 hours after admission and was 1.54 μg / ml, the mean AUC (area under the concentration-time curve) is 76.4 ± 20.3 μg / h / ml and the average T1 / 2 is 46.2 hours. The values of these pharmacokinetic parameters are higher than in young patients, which is probably , is associated with a decreased renal function,characteristic of the elderly. Simultaneous reception of diuretics did not cause a pronounced change in AUC and Cmax.

Kk (74 ml / min), the percentage of fluconazole outputted by the kidneys in an unmodified form (0-24 h, 22%) and renal clearance fluconazole (0.124 mL / min / kg) lower than in older patients as compared with the young.

Indications:

Fluconazole STADA is indicated for the treatment of the following diseases in adults:

acute vaginal candidiasis, when local therapy is not applicable;
Candidiasis balanitis, when local therapy is not applicable;
dermatomycosis, incl. dermatophytosis of the feet, trunk dermatophyte, inguinal dermatophytosis, pityrious (multicolored) lichen and skin candidiasis infections when systemic treatment is indicated;
nail dermatophytosis (onychomycosis), when treatment with other drugs is not acceptable.

Fluconazole STADA is indicated for the prevention of the following diseases in adults:

relapse of oropharyngeal candidiasis in HIV-infected patients with a high risk of recurrence;
to reduce the frequency of recurrences of vaginal candidiasis (4 or more episodes per year).

Contraindications:

Hypersensitivity to fluconazole, other components of the drug or azole compounds with a similar fluconazole structure.
Simultaneous reception of terfenadine (against the background of a constant intake of fluconazole at a dose of 400 mg / day or more); simultaneous use with drugs that increase the QT interval and metabolized with the isoenzyme CYP3A4, such as cisapride, astemizole, erythromycin, pisomide and quinidine (see section "Interaction with other drugs"),
Renal failure (CC less than 50 ml / min).
The period of breastfeeding.
Children under 18 years.
Lactose intolerance, lactase deficiency, glucose-galactose malabsorption (the preparation contains lactose).

Carefully:

Hepatic and / or renal insufficiency (SC more than 50 ml / min), the appearance of rash against the background of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections, concurrent administration of terfenadine and fluconazole in a dose of less than 400 mg / day, hepatotoxic drugs, alcoholism, potentially proaritmogenic states in patients with multiple risk factors (organic heart disease, electrolyte balance disorders, simultaneous administration of the drug idents means causing arrhythmias), pregnancy.

Pregnancy and lactation:

Adequate and controlled studies of the use of fluconazole in pregnant women have not been conducted. Several cases of multiple congenital malformations in newborns have been described, whose mothers received high-dose fluconazole (400-800 mg / day) for most or all of the first trimester. The following developmental disorders were noted: brachycephaly, violation of the front part of the skull, a violation of the formation of the cranial vault, a cleft palate, the curvature of the femoral bone thinning and elongation of the ribs, arthrogryposis and congenital heart defects. There is currently no evidence linking listed congenital anomalies using a low dose of fluconazole (150 mg once daily for the treatment of vulvovaginal candidiasis) in the first trimester of pregnancy.

During pregnancy, fluconazole should be avoided, except in cases of severe and potentially life-threatening fungal infections, when the expected benefit of treatment for the mother exceeds the possible risk to the fetus. Women of childbearing age should use contraception.

Since the concentration of fluconazole in breast milk and in plasma is the same,Apply the drug during breastfeeding is contraindicated.

Dosing and Administration:

Inside, swallowing whole.

With vaginal candidiasis fluconazole taken once inside the dose of 150 mg. With balanitis caused by Candida, fluconazole is administered orally once a dose of 150 mg.

With skin dermatomycosis, including dermatophytosis of the feet, trunk, inguinal area, the recommended dose is 150 mg once a week, the dosage regimen depends on the clinical and mycological effect. Duration of therapy in usual cases is 2-4 weeks, however, with stop dermatophytosis, longer therapy (up to 6 weeks) may be required.

With pityriasis, 300 mg (2 capsules of 150 mg) once a week for 2 weeks, some patients require a third dose of 300 mg per week, while in some cases a single 300 dose is sufficient.

With onychomycosis, the recommended dose is 150 mg once a week. Treatment should continue until the replacement of the infected nail (growth of uninfected nail). For the repeated growth of the nails on the fingers and feet normally it takes 3-6 months and 6-12 months, respectively.

To prevent the recurrence of oropharyngeal candidiasis in HIV-infected patients - 150 mg once a week.

To reduce the frequency of recurrences of vaginal candidiasis, the drug is taken in a dose of 150 mg once a month. The duration of therapy is determined individually; it varies from 4 to 12 months. Some patients may need more frequent use.

In elderly patients in the absence of violations of kidney function should follow the usual dosage regimen.

Side effects:

On the part of the intestinal tract: decreased appetite, changes in taste, nausea, vomiting, abdominal pain, flatulence, diarrhea, constipation, dyspepsia, dryness of the oral mucosa;

On the part of the liver and bile ducts: hepatotoxicity, in some cases fatal, hepatocellular damage, hyperbilirubinemia, increased activity of alanine aminotransferase, aspartate aminotransferase, increased activity of alkaline phosphatase, jaundice, hepatitis, hepatocellular necrosis, cholestasis.

From the nervous system: headache, dizziness, convulsions, paresthesia, insomnia, drowsiness, tremor.

From the hematopoiesis: anemia, leukopenia, thrombocytopenia

(bleeding, petechiae), neutropenia, agranulocytosis.

From the cardiovascular system: an increase in the duration of the QT interval, arrhythmia ventricular tachysystolic type "pirouette" (torsades de pointes) (see section "Special instructions").

From the skin: alopecia, increased sweating, exfoliative skin lesions, acute generalized exanthematous pustulosis, drug rash.

From the musculoskeletal system: myalgia.

From the side of metabolism: increased concentration of cholesterol and triglycerides in blood plasma, hypokalemia.

Allergic reactions: skin rash, multiforme exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), anaphylactoid reactions (including angioedema, edema of the face, urticaria, skin itching).

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

In some patients, especially those suffering from serious diseases, such as AIDS or cancer, fluctuations in blood counts, kidney and liver function were observed in the treatment of fluconazole and similar drugs (see Fig.section "Special instructions"), but the clinical significance of these changes and their relationship to treatment are not established.

Overdose:

Symptoms: hallucinations, paranoid behavior.

Treatment: symptomatic. Gastric lavage, forced diuresis. Hemodialysis within 3 hours reduces the plasma concentration by approximately 50%.

Interaction:

Contraindicated simultaneous use of fluconazole with the following drugs'.

Astemizole. The simultaneous use of fluconazole with astemizole or other drugs metabolized by the cytochrome P450 system may be accompanied by an increase in the serum concentrations of these agents. Elevated concentrations of astemizole in the blood plasma can lead to lengthening of the QT interval and in some cases to the development of the ventricular tachycystolic type artifact (torsades de pointes). The simultaneous use of fluconazole and astemizole is contraindicated.

Pimozide. Although no appropriate in vitro or in vivo studies have been performed, the simultaneous use of fluconazole and pimozide can lead to inhibition of the metabolism of pimozide. In turn, an increase in plasma concentrations of pimozidecan lead to an elongation of the QT interval and, in some cases, the development of a torsades de pointes ventricular tachycystolic type arrhythmia. The simultaneous use of fluconazole and pimozide is contraindicated.

Terfenadine. Simultaneous use of azole antifungal agents and terfenadine can lead to a significant increase in the concentration of terfenadine in the plasma: serious arrhythmias can occur as a result of an increase in the QT interval. The simultaneous use of fluconazole at a dose of 400 mg / day or more and terfenadine is contraindicated.

Quinidine. Despite the fact that no appropriate in vitro or in vivo studies have been conducted, the simultaneous use of fluconazole and quinidine may lead to inhibition of quinidine metabolism. The use of quinidine is associated with lengthening of the QT interval and in some cases with the development of torsades de pointes ventricular tachysystolic type arrhythmia. The simultaneous use of fluconazole and quinidine is contraindicated.

Cisapride. With simultaneous application of fluconazole and cisapride, the concentration of cisapride in plasma can increase significantly; cases of unwanted reactions from the heart are described, incl.fibrillation / flutter of the ventricles including (torsades de pointes), increase in the QT interval on the electrocardiogram (ECG). The simultaneous use of fluconazole and cisapride is contraindicated.

Erythromycin. The simultaneous use of fluconazole and erythromycin potentially leads to an increased risk of cardiotoxicity (prolongation of the QT interval, torsades de pointes) and, as a result, sudden cardiac death. The simultaneous use of fluconazole and erythromycin is contraindicated.

Care must be taken and. it is possible to adjust the dose with simultaneous use of the following drugs and fluconazole:

Drugs affecting fluconazole:

Hydrochlorothiazide. Simultaneous use of fluconazole and hydrochlorothiazide can lead to an increase in the concentration of fluconazole in plasma by 40%.

Rifampicin. The combination with rifampicin leads to a 25% reduction in AUC and a 20% decrease in the half-life of fluconazole from the plasma. Therefore, patients receiving concomitantly rifampicin, it is advisable to increase the dose of fluconazole. Drugs affected by fluconazole:

Fluconazole is a potent inhibitor of the CYP2C9 isoenzyme cytochrome P450 and a moderate inhibitor of the CYP3A4 isoenzyme.In addition, in addition to the effects listed below, there is a risk of an increase in plasma concentrations of other drugs metabolized by CYP2C9 and CYP3A4 isoenzymes while being administered with fluconazole. In this regard, caution should be exercised when using these drugs at the same time, and if necessary, such combinations should be carefully monitored by patients. It should be borne in mind that the inhibitory effect of fluconazole persists for 4-5 days after discontinuation of the drug due to a prolonged half-life. Azithromycin. With the simultaneous administration of fluconazole in a single dose of 800 mg with azithromycin in a single dose of 1200 mg expressed pharmacokinetic interaction between both drugs is not established.

Vinca alkaloids. Despite the lack of targeted research, it is assumed that fluconazole can increase the concentration of vinca alkaloids (eg, vincristine and vinblastine) in the blood plasma and, thus, lead to neurotoxicity, which may possibly be due to inhibition of the CYP3A4 isoenzyme.

Alfentanil.There is a decrease in clearance and volume of distribution, an increase in the half-life of alfentanil. Perhaps this is due to the inhibition of the isoenzyme CYP3A4 by fluconazole. Alfventanyl dosage adjustment may be required. Amitriptyline, nortriptyline. There is an increase in the effect. The concentration of 5-nortriptyline and / or S-amitriptyline can be measured at the onset of combination therapy with fluconazole and a week after initiation. If necessary, adjust the dose of amitriptyline / nortriptyline.

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

Short-acting benzodiazepia (midazolam, triazolam). After ingestion of midazolam fluconazole significantly increases the concentration of midazolam and psychomotor effects, and this effect is more pronounced after taking fluconazole orally than with its use intravenously. If concomitant therapy with benzodiazepines is required in patients taking fluconazole, should be monitored to assess the appropriateness of an appropriate dose reduction for benzodiazepine.

With the simultaneous administration of a single dose of triazolam fluconazole increases the AUC of triazolam by approximately 50%, Cmax by 25-50% and T1 / 2 by 25-50%, due to inhibition of triazolam metabolism. You may need to adjust the dose of triazolam.

Blockers of "slow" calcium channels. Some antagonists of calcium channels (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by the isoenzyme CYP3A4. Fluconazole increases the systemic exposure of calcium channel antagonists. It is recommended to control the development of side effects.

Warfarin. When using fluconazole with warfarin, prothrombin time increases (on average by 12%). In this regard, it is recommended to carefully monitor the prothrombin time in patients receiving the drug in combination with coumarin anticoagulants.

Vitamin A. There is a report of one case of development of undesirable reactions from the central nervous system (CNS) in the form of a pseudotumor of the brain with the simultaneous use of fully transretinic acid and fluconazole, which disappeared after the withdrawal of fluconazole.The use of this combination is possible, but one should remember about the possibility of undesirable reactions from the CNS.

Voriconazole (inhibitor of isoenzymes CYP2C9, CYP2C19 and CYP3A4). The simultaneous use of voriconazole (400 mg twice a day on the first day, then 200 mg twice daily 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 reduction in the dose and / or a decrease in the frequency of administration of any of the drugs. Simultaneous use of voriconazole and fluconazole is not recommended. Halofantrine. Fluconazole can increase the concentration of halophanthin in the blood plasma in connection with the inhibition of the isoenzyme CYP3A4.

Zidovudine. In patients receiving a combination of fluconazole and zidovudine, there is an increase in zidovudine concentration, which is caused by a decrease in the conversion of the latter into its main metabolite, so you should expect an increase in the side effects of zidovudine.

Inhibitors of HMG-CoA reductase. With the simultaneous use of fluconazole with HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme (such as atorvastatin and simvastatin) or the isoenzyme CYP2D6 (such as fluvastatin), the risk of developing myopathy and rhabdomyolysis increases. In case of need for simultaneous therapy with these drugs, patients should be observed to identify the symptoms of myopathy and rhabdomyolysis. It is necessary to monitor the concentration of creatinine kinase. In the case of a significant increase in the concentration of creatinine kinase or if there is a diagnosis or suspected development of myopathy or rhabdomyolysis, therapy with HMG-CoA reductase inhibitors should be discontinued.

Carbamazepine. Fluconazole It inhibits the metabolism of carbamazepine and increases the serum concentration of carbamazepine by 30%. It is necessary to consider the risk of development of toxicity of carbamazepine. It is necessary to evaluate the need for correcting the dose of carbamazepine as a function of concentration / effect.

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-P receptors. Regular monitoring of blood pressure is necessary. Methadone. Fluconazole can increase the plasma concentration of methadone.Methadone dose adjustment may be necessary.

Non-steroidal anti-inflammatory drugs (NSAIDs). Stach and AUC of flurbiprofen increase by 23% and 81%, respectively. Similarly, Cmax and AUC of the pharmacologically active isomer [8 - (+) - ibuprofen] increased by 15% and 82%, respectively, while fluconazole was simultaneously administered with racemic ibuprofen (400 mg).

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

With the simultaneous use of NSAIDs and fluconazole, patients should be carefully monitored to detect and control adverse events and toxicity associated with NSAIDs.

Oral hypoglycemic agents - derivatives of sulfonylureas (chlorpropamide, glibenclamide, glipizide, tolbutamide). It is possible to increase the half-life oral hypoglycemic agents - derivatives of sulfonylureas with simultaneous administration with fluconazole.

Oral contraceptives.At simultaneous application of the combined oral contraceptive with fluconazole at a dose of 50 mg there is no significant effect on the level of hormones, whereas with the daily intake of 200 mg fluconazole, the AUC of ethinylestradiol and levonorgestrel is increased by 40% and 24% respectively, and when 300 mg of fluconazole is administered once The week of AUC of ethinyl estradiol and norethindrone increases by 24% and 13%, respectively. Thus, the repeated use of fluconazole at these doses is unlikely to affect the effectiveness of the combined oral contraceptive.

Prednisone. There is a report on the development of acute adrenocortical insufficiency in a patient after liver transplantation with a withdrawal of fluconazole after a three-month course of therapy. Presumably, discontinuation of fluconazole therapy caused an increase in the activity of the isoenzyme CYP3A4, which led to an increased metabolism of prednisone. Patients receiving combination therapy with prednisone and fluconazole should be carefully monitored when fluconazole is withdrawn to evaluate the condition of the adrenal cortex.

Rifabutin.There are reports of the interaction of fluconazole and rifabutin, accompanied by an increase in serum concentrations of the latter. With the simultaneous use of fluconazole and rifabutin, cases of uveitis are described. It is necessary to carefully observe patients who are simultaneously receiving rifabutin and fluconazole.

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

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

Tacrolimus. Fluconazole increases the concentration of tacrolimus, in connection with which the risk of nephrotoxic action increases. Patients simultaneously taking tacrolimus inside and fluconazole, should be carefully observed.The dose of tacrolimus should be adjusted depending on the degree of increase in its concentration in the blood. Theophilia. In the case of simultaneous application with theophylline, the average rate of clearance of theophylline from the plasma may decrease. In the administration of fluconazole to patients receiving theophylline in high doses, or in patients at increased risk of developing the toxic effect of theophylline, the symptoms of an overdose of theophylline should be monitored and, if necessary, adjusted accordingly.

Tofacitinib. Exposure tofacitinib increases with its combination with drugs that are both moderate inhibitors of the CYP3A4 isoenzyme and potent inhibitors of the CYP2C19 isoenzyme (for example, fluconazole). It may be necessary to correct the dose of tofacitinib.

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

Fentanyl.There is a report of one fatal outcome, possibly associated with simultaneous administration of fentanyl and fluconazole. It is assumed that the violations are associated with intoxication with fentanyl. It was shown that fluconazole significantly prolongs the excretion time of fentanyl. It should be borne in mind that an increase in the concentration of fentanyl may lead to inhibition of respiratory function.

Celecoxib. With the simultaneous use of fluconazole at a dose of 200 mg / day and celecoxib at a dose of 200 mg, Stach and AUC of celecoxib are increased by 68% and 134%, respectively. In this combination, a dose reduction of celecoxib can be halved. Cyclosporin. It is possible to increase the concentration of cyclosporine with simultaneous application with fluconazole at a dose of 200 mg / day.

Cyclophosphamide. With the simultaneous use of cyclophosphamide and fluconazole, there is an increase in serum concentrations of bilirubin and creatinine. This combination is acceptable given the risk of increasing concentrations of bilirubin and creatinine.

The above interactions were established with repeated application of fluconazole; interactions with drugs as a result of a single administration of fluconazole are not known.Doctors should take into account that interaction with other drugs has not been specifically studied, but it is possible. Investigations of the interaction of oral forms of fluconazole with its simultaneous administration with food, cimetidine, antacids, and after total body irradiation for the preparation of bone marrow transplantation showed that these factors do not have a clinically significant effect on the absorption of fluconazole.

Special instructions:

Treatment should continue until the appearance of clinical-hematologic remission. Premature termination of treatment leads to relapse.

In rare cases, the use of fluconazole was accompanied by toxic changes in the liver, incl. with a fatal outcome, mainly in patients with serious concomitant diseases. In the case of hepatotoxic effects associated with fluconazole, there was no apparent dependence on the total daily dose, duration of therapy, sex, and age of the patient. The hepatotoxic effect of fluconazole was usually reversible; signs of it disappeared after discontinuation of therapy. If there are clinical signs of liver damage that may be associated with fluconazole, the drug should be discontinued.

Patients with AIDS are more likely to develop severe skin reactions with many drugs. In those cases where the rash develops in patients with superficial fungal infection and it is regarded as definitely associated with fluconazole, the drug should be discontinued. When rashes appear in patients with invasive / systemic fungal infections, they should be carefully monitored and canceled fluconazole when there are bullous changes or erythema multiforme. There have been reports of superinfection caused by Candida strains other than Candida albicans, which often have a natural resistance to fluconazole (eg, Candida krusei). In such cases, alternative antifungal therapy may be required.

Simultaneous use of fluconazole in doses less than 400 mg / day and terfenadine should be carried out under close supervision (see section "Interaction with other drugs").

Caution should be exercised while taking fluconazole with rifabutin or other drugs metabolized by the cytochrome P-450 system.

When combined with fluconazole and oral hypoglycemic agents (chlorpropamide, glibenclamide, glipizide, tolbutamide) in patients with diabetes should monitor blood glucose (the possibility of developing hypoglycemia). It is recommended to monitor the concentration of cyclosporine in the blood with simultaneous application with fluconazole.

Patients who receive high doses of theophylline concomitantly with fluconazole, or who have a chance of developing theophylline intoxication, should be monitored for the early detection of symptoms of theophylline overdose.

Like other azoles, fluconazole can cause an increase in the QT interval on the ECG. With fluconazole, an increase in the QT interval and fibrillation or flutter of the ventricles were very rare in patients with severe diseases with multiple risk factors, such as organic heart disease, electrolyte imbalance, and concomitant therapy contributing to the development of such disorders. Therefore, in such patients with potentially proarrhythmic conditions, fluconazole with caution.

Patients with diseases of the liver, heart and kidneys are advised to consult a doctor before using the drug.

When fluconazole 150 mg is used for vaginal candidiasis, the patient should be warned that symptom improvement is usually observed after 24 hours, but to completely disappear, it sometimes takes several days. If symptoms persist for several days, you should consult your doctor.

Effect on the ability to drive transp. cf. and fur:

The experience of using the drug showed that fluconazole usually does not affect the ability to drive vehicles and mechanisms. However, in case of dizziness in the patient, drowsiness during taking the drug should be avoided by practicing potentially dangerous activities.

Form release / dosage:

Capsules 150 mg.

Packaging:

For 1 or 7 capsules in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered. 1 circuit cell pack together with instructions for use in a pack of cardboard.

Storage conditions:

In a dry, protected from light place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:P N001955 / 01

Date of registration:15.12.2008

The owner of the registration certificate:Nizhny Novgorod Chemical and Pharmaceutical Plant, OJSCNizhny Novgorod Chemical and Pharmaceutical Plant, OJSC

Manufacturer: & nbsp

MAKIZ-PHARMA, LLC Russia

HEMOFARM, LLC Russia

Representation: & nbspNizhpharm, JSCNizhpharm, JSCRussia

Information update date: & nbsp15.10.2015

Illustrated instructions

Instructions

Fluconazole STADA (Fluconazole STADA)