Mikoflukan - instructions for use, dose, side effects, contraindications

Excipient: cellulose microcrystalline - 22.75 mg, lactose - 30 mg, croscarmellose sodium - 5.75 mg, povidone K30 - 4 mg, silicon dioxide colloid - 0.75 mg, magnesium stearate - 0.75 mg, talc purified - 1 mg .

Each 150 mg tablet contains:

Active substance: fluconazole - 150 mg.

Excipients: cellulose microcrystalline 68.25 mg, lactose 90 mg, croscarmellose sodium 17.25 mg, povidone K30 12 mg, silicon dioxide colloid 2.25 mg, magnesium stearate 2, 25 mg, talc purified 3 mg.

Description:

50 mg tablets

White or almost white, flat-faced tablets with chamfer, with an impression "F" on one side and "50" on the other side.

150 mg tablets

White or almost white, flat-faced tablets with a bevel, with an impression "F150" on one side and a separation risk on the other side.

Pharmacotherapeutic group:Antifungal agent

ATX: & nbsp

J.02.A.C Triazole derivatives

J.02.A.C.01 Fluconazole

Pharmacodynamics:

Representative of a new class of triazole antifungal agents. Has a highly specific effect, inhibiting the activity of enzymes of fungi, dependent on cytochrome P450; Blocking the conversion of lanosterol of fungal cells to 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 to a lesser extent suppresses oxidative processes dependent on cytochrome P450 in human liver microsomes).Does not have antiadrogenic activity.

It is active in opportunistic mycoses, including those 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 cap'sulatum (including immunosuppression).

Pharmacokinetics:

Suction

After oral administration fluconazole is well absorbed, its plasma levels (and overall bioavailability) exceed 90% of plasma fluconazole levels when administered intravenously. Simultaneous food intake does not affect the absorption (absorption) of the drug when ingested. The time to reach the maximum concentration (T_Cmah) after oral administration of 150 mg of fluconazole 0.5-1.5 hours and is 90% of the plasma concentration for intravenous administration at a dose of 2.5-3.5 mg / l.

Distribution

The concentration in the plasma is in direct proportion to the dose. About 90% of the equilibrium concentration of the drug in plasma (Css) is reached by the 4-5 day of intake (once taken once a day). The introduction of a "shock" dose (on the first day), which is 2 times greater than the usual daily dose, allows one to achieve a concentration corresponding to 90% Css by day 2. 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. It penetrates well into the cerebrospinal fluid (CSF); in fungal meningitis, the concentration in the CSF is about 85% of that in the plasma. In the liquid of the sweat, the dermis and the stratum corneum (selective accumulation), high concentrations are reached that exceed the serum levels. When administered at a dose of 50 mg once a day, the concentration of fluconazole after 12 days was 73 μg / g, and after 7 days after discontinuation of treatment it was 5.8 μg / l. After ingestion 150 mg 1 time per week. - On day 7, the fluconazole concentration in the stratum corneum was 23.4 μg / g, and 7 days after the second dose, 7.1 μg / g.

Concentration in the nails after 4 months of use in a dose of 150 mg once a week: in healthy nails - 4.05 μg / g, in the affected - 1.8 μg / g. After 6 months. after completion of therapy, fluconazole was still determined in the nails.

Apparent volume of distribution (Vd) is close to the total water content in the body.The connection with plasma proteins is low - 11-12%.

Metabolism and excretion

The half-life (T_1/2) - 30 hours. It is an inhibitor of the isoenzyme CYP2C9 in the liver. It is excreted primarily by the kidneys (80% - unchanged, 11% - in the species metabolites). The clearance of fluconazole is proportional to the creatinine clearance.

The pharmacokinetics of fluconazole significantly depends on the functional state of the kidneys, and there is an inverse relationship between T_1/2 and clearance of creatinine (QA). After hemodialysis, within 3 hours, the concentration of fluconazole in the plasma is reduced by 50%.

The pharmacokinetics of fluconazole is similar for intravenous administration and oral administration, which makes it easy to switch from one type of reception to another.

Indications:

-System damage caused by Cryptococcus fungi, including meningitis, sepsis, lung and skin infections, both in patients with normal immune response, and in patients with various forms of immunodepression (including AIDS patients, transplant recipients); Supportive therapy for the prevention of cryptococcal infection in AIDS patients.

Generalized candidiasis: candidemia, disseminated candidiasis (with damage to the eyes, endocardium, abdominal organs,respiratory organs, and urogenital organs), the speech can be performed in patients with malignant neoplasms and receiving a course of cytostatic or immunosuppressive therapy, as well as in the presence of other factors predisposing to their development treatment and prevention.

Candidiasis of the mucous membranes: oral cavity, pharynx, esophagus, non-invasive bronchopulmonary candidiasis, candiduria, mucocutaneous and chronic oral atrophic candidiasis (associated with wearing dentures); prevention of recurrence of oropharyngeal candidiasis in AIDS patients;

Genital candidiasis: vaginal (acute and recurrent). Prophylactic use to reduce the frequency of recurrence of vaginal candidiasis (three or more episodes per year). Candidiasis balanitis.

-Prevention of fungal infections in patients with malignant tumors on the background of chemo- or radiation therapy; prevention of recurrence of oropharyngeal candidiasis in AIDS patients.

- Mycosis of the skin: foot, body, groin, onychomycosis, pityriasis, skin candidiasis infections.

Deep endemic mycoses (coccidiomycosis, paracoccidiomycosis, sporotrichosis and histoplasmosis) in patients with normal immunity.

Contraindications:

Hypersensitivity to the components of the drug (including other azole antifungal drugs); simultaneous reception of terfenadine (against the background of continuous administration of fluconazole at a dose of 400 mg / day or more) or astemizole; lactation period.

Carefully:

Children up to 3 years of age are recommended to use fluconazole in the form of a solution for infusions, syrup, or powder to prepare a suspension for oral administration, rather than solid dosage forms. Liver failure, occurrence of rash on the background of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections, simultaneous terfenadine and fluconazole to a dose of less than 400 mg / day, potentially proaritmogennoe condition in a patient with multiple risk factors (organic heart diseases, disorders electrolyte balance, simultaneous intake of drugs that cause arrhythmias), pregnancy.

Pregnancy and lactation:

Avoid the use of fluconazole in pregnancy, except in cases of severe and potentially life-threatening fungal infections, when the expected benefit of fluconazole for the mother significantly exceeds the possible risk to the fetus.Since fluconazole concentration in breast milk and plasma is the same, to apply the drug during lactation - is contraindicated.

Dosing and Administration:

The daily dose of fluconazole depends on the nature and severity of the fungal infection.

Adults and children over 15 years of age (body weight over 50 kg)

When Cryptococcal meningitis and cryptococcal infections of other sites in the first day, 400 mg is usually prescribed, and then continue treatment at a dose of 200-400 mg once / day. The duration of treatment for cryptococcal infections depends on the clinical efficacy, confirmed by mycological examination; with cryptococcal meningitis, it usually lasts a minimum of 6-8 weeks.

For prevention of recurrence of cryptococcal meningitis in patients with AIDS, after completion of the full course of primary treatment, fluconazole therapy is continued at a dose of 200 mg / day for a long period of time.

When candidemia, disseminated candidiasis and other invasive candidiasis infections the dose is 400 mg in the first day, and then - at 200 mg / day. With insufficient clinical efficacy, the dose of fluconazole can be increased to 400 mg / day.The duration of therapy depends on clinical effectiveness.

When oropharyngeal candidiasis appoint 150 mg once a day for 7-14 days. If necessary, in patients with a marked decrease in immunity, treatment may be longer.

For prevention of recurrences of oropharyngeal candidiasis in patients with AIDS, after completion of the full course of primary therapy, fluconazole can be prescribed for 150 mg once a week.

When atrophic candidiasis of the oral cavity associated with the wearing of dentures, appoint 50 mg 1 time / day for 14 days in combination with local antiseptic agents for prosthesis treatment.

When other localizations of candidiasis (with the exception of genital candidiasis), for example, with esophagitis, non-invasive bronchopulmonary disease, candiduria, candidiasis of the skin and mucous membranes, the effective dose of fluconazole is 150 mg / day, with a treatment duration of 14-30 days.

When vaginal candidiasis appoint a single oral dose of 150 mg. Fordecrease in the frequency of recurrences of vaginal candidiasis the drug can be used 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 require more frequent use of fluconazole.

When balanitis caused by Candida, appoint a single dose of 150 mg orally.

For prevention of candidiasis the recommended dose is 50-400 mg 1 time / day, depending on the degree of risk of fungal infection. When high risk of generalized infection, for example, in patients with expected severe or persistent neutropenia, the recommended dose is 400 mg 1 time / day. The drug is prescribed a few days before the expected appearance of neutropenia; after an increase in the number of neutrophils more than 1000 / mm³ treatment is continued for another 7 days.

When mycosis skin, including mycosis stop, smooth skin and skin inguinal area,the recommended dose is 150 mg once a week or 50 mg 1 time / day. The duration of therapy in usual cases is 2-4 weeks, however, with foot mycoses, longer therapy (up to 6 weeks) may be required.

When pityriasis the recommended dose is 300 mg once a week for 2 weeks. Some patients require a third dose of 300 mg per week, while in some cases it is sufficient to receive 300-400 mg once daily.

An alternative treatment regimen is the use of the drug at 50 mg once a day for 2-4 weeks.

When onychomycosis the recommended dose of fluconazole is 150 mg once a week. Treatment should continue until the replacement of the infected nail (growth of uninfected nail). To re-grow the nails on the fingers and toes, it normally takes 3-6 months and 6-12 months, respectively. However, the growth rate can vary widely among different people, and also depending on age.

When deep endemic mycoses may require the use of the drug at a dose of 200-400 mg / day for up to 2 years. The duration of therapy is determined individually; it can be coccidiomycosis 11-24 months; atparacoccidiosis - 2-17 months; at sporotrichosis - 1-16 months and with histoplasmosis - 3-17 months.

Have children, as with similar infections in adults, the duration of treatment depends on the clinical and mycological effect. In children, the drug should not be used in a daily dose that would exceed that of adults, that is, not more than 400 mg / day. The drug is used daily 1 time / day.

When esophageal candidiasis appoint once in a daily dose of 3 mg / kg, in the following average doses: at the age of 3-6 years (body weight 15-20 kg) - 50 mg; at the age of 7-9 years (body weight 21-29 kg) - 50-100 mg; at the age of 10-12 years (body weight 30-40 kg) - 100-150 mg; at the age of 12-15 years (body weight 40-50 kg) - 100-150 mg.The duration of the therapy is at least 3 weeks and 2 weeks after the regression of the symptoms.

When candidiasis of mucous membranes appoint once in a daily dose of 3 mg / kg, in the following average doses: at the age of 3-6 years (body weight 15-20 kg) - on the first day 100-150 mg, then - 50 mg; at the age of 7-9 years (body weight 21-29 kg) - on the first day 100-200 mg, then - 100 mg; at the age of 10-12 years (body weight 30-40 kg) - on the first day 100-150 mg, then - 50-100 mg each; at the age of 12-15 years (body weight 30-40 kg) - on the first day 250-300 mg, then - for 100-150 mg. The duration of therapy is at least 3 weeks.

When generalized candidiasis and cryptococcal infection (including meningitis)appoint once in a daily dose of 6-12 mg / kg, in the following average doses: at the age of 3-6 years (body weight 15-20 kg) - 100-250 mg; at the age of 7-9 years (body weight21-29 kg) - 100-300 mg; at the age of 10-12 years (body weight 30-40 kg) - 200-350 mg; at the age of 12-15 years (body weight 40-50 kg) - 250-400 mg. Duration of therapy - for 10-12 weeks (before laboratory confirmation of the absence of pathogens in the cerebrospinal fluid).

For the prevention of fungal infections in children with reduced immunity, at which the risk of infection is associated with neutropenia, resulting from cytotoxic chemotherapy or radiation therapy, the drug is administered once in a daily dose of 3-12 mg / kg,in the following average doses: at the age of 3-6 years (body weight 15-20 kg) - 50-250 mg; at the age of 7-9 years (body weight 21-29 kg) - 50-300 mg; at the age of 10-12 years (body weight 30-40 kg) - 100-350 mg; at the age of 12-15 years (body weight 40-50 kg) - 100-400 mg. The duration of therapy is until elimination of induced neutropenia.

In children with impaired renal function the daily dose of the drug should be reduced (in the same proportional relationship as in adults), in accordance with the degree of renal failure.

Application in the elderly

In the absence of violations of the kidneys should follow the usual dosage regimen.

Patients with renal impairment (creatinine clearance less than 50 mL / min) dosing regimen should be adjusted as indicated below.

The use of the drug in patients with impaired renal function

Fluconazole is excreted mainly with urine in an unchanged form. With a single admission, a dose change is not required. When re-administering the drug, patients with impaired renal function should first enter a shock dose of 50 to 400 mg; with CK> 40 ml / min fluconazole applied 1 time / day in a usual dose. With SC 21-40 ml / min - with an interval of 48 hours (1 every 2 days) or 1 time / day in half the usual daily dose; with KK 10-20 ml / min - with an interval of 72 hours (1 every 3 days) or 1 time / day in a daily dose equal to one third of the estimated.Patients regularly on dialysis, one dose of the drug is used after each session of hemodialysis.

Side effects:

Mycoflucan^®, as a rule, well tolerated.

Depending on the frequency of occurrence, the following groups of side effects are distinguished: often (more than 1%), infrequently (0.1-1%), rarely (0.01-0.1%), very rarely (less than 0.01%).

Allergic reactions: infrequent skin rash; rarely - multi-form exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), anaphylactoid reactions (including angioedema, facial edema, urticaria, skin itching).

From the side of the central nervous system: infrequently - headache, dizziness; rarely convulsions.

From the digestive system: infrequently - nausea, diarrhea, flatulence, abdominal pain, taste change, vomiting; rarely - a violation of liver function (jaundice, hyperbilirubinemia, increased activity of ALT, ACT and APF, hepatitis, hepatocellular necrosis), incl. with a lethal outcome.

From the hematopoiesis: rarely - leukopenia, thrombocytopenia, neutropenia, agranulocytosis.

From the cardiovascular system: rarely - an increase in the duration of the QT interval, flicker / flutter of the ventricles.

Other: rarely - renal dysfunction, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Overdose:

Symptoms: hallucinations, paranoid behavior.

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

Interaction:

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

The simultaneous use of fluconazole with the following drugs is contraindicated

Cisapoid: in the single-valued application of fluconazole and cisapride, undesirable reactions from the heart are possible, incl. arrhythmia ventricular tachysystolic type "pirouette" (torsade de pointes). 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.

Simultaneous administration of cisapride and fluconazole is contraindicated.

Terfenadine: the simultaneous use of azole antifungal agents and terfenadine may cause serious arrhythmias as a result of an increase in the QT interval.

When receiving Fluconazole, 200 mg / day increasing QT interval is not set, but the use of fluconazole in doses of 400 mg / day and above causes a significant increase in the concentration of terfenadine in the blood plasma. Simultaneous administration of fluconazole in doses of 400 mg / day or more with terfenadine is contraindicated (see section "Contraindications"), "Treatment with fluconazole at doses less than 400 mg / day in combination with terfenadine should be carefully monitored.

Astemizole: the simultaneous use of fluconazole with astemizole or other drugs metabolized by isoenzymes of 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 the development of torsade de pointes ventricular tachycystolic type arrhythmia. Simultaneous use of astemizole and fluconazole is contraindicated.

Quinidine: Although no appropriate in vitro or in vivo studies have been performed, the simultaneous use of fluconazole and quinidine may also lead to inhibition of quinidine metabolism.The use of quinidine is associated with prolongation of the QT interval and, in some cases, with the development of torsade de pointes, a ventricular tachysystolic type arrhythmia. Simultaneous use of quinidine and fluconazole is contraindicated.

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

Care should be taken and, possibly, dose adjustments should be made while using the following drugs and fluconazole

Drugs affecting fluconazole

Hydrochlorothiazide: repeated application of hydrochlorothiazide simultaneously with fluconazole leads to an increase in the concentration of fluconazole in blood plasma by 40%. The effect of this degree of expression 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: simultaneous application of fluconazole and rifampicin leads to a decrease in the area under the pharmacokinetic curve "concentration-time" (AUC) by 25% and the duration of the half-life (T_1/2) of fluconazole by 20%. In patients who simultaneously take rifampicin, it is necessary to consider the advisability of increasing the dose of fluconazole.

Drugs affected by fluconazole

Fluconazole is a potent inhibitor of the CYP2C9 and CYP2C19 isoenzymes cytochrome P450 and a moderate inhibitor of the CYP3A4 isoenzyme. In addition, in addition to the effects listed below, there is a risk of elevated concentrations in the blood plasma and other drugs metabolized by the CYP2C9, CYP2C19 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 noted that the inhibitory effect of fluconazole persists for 4-5 days after discontinuation of the drug due to prolonged T_1/2.

Alfentanil: there is a decrease in clearance and volume of distribution (V_d), an increase in T_1/2 alfentanil. Perhaps this is due to the inhibition of the isoenzyme CYP3A4 by fluconazole. It may be necessary to adjust the dose of alfentanil

Amitriptyline, nortriptyline: increase the effect. The concentration of 5-nortriptyline and / or S-amitriptyline can be measured at the onset of combination therapy with fluconazole and a week after initiation.If necessary, adjust the dose of amitriptyline / nortriptyline

Amphotepicin B: In studies on mice (including immunosuppression), the following results were noted: a slight additive antifungal effect in systemic infection caused by Candida 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.

Anticoagulants: like other antifungal agents (azole derivatives), fluconazole with simultaneous application with warfarin increases prothrombin time (by 12%), in connection with which bleeding may develop (hematomas, nosebleeds and digestive tract, hematuria, melena). In patients receiving coumarin anticoagulants and fluconazole it is necessary to constantly monitor prothrombin time during therapy and within 8 days after simultaneous use. Also, the appropriateness of correcting the dose of warfarin should be evaluated.

Azithromycin: single-dose application of fluconazole in a single dose of 800 mg with azithromycin in a single dose of 1200 mg of pronounced pharmacokinetic interaction is not 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 orally than with its use intravenously. If concomitant therapy with benzodiazepines is necessary for patients taking fluconazole should be observed 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%, the maximum concentration in serum (C_max) - by 25-50% and T_1/2 by 25-50% due to inhibition of the metabolism of triazolam. You may need to adjust the dose of triazolam.

Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and increases the concentration of carbamazepine in plasma 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.

Calcium channel blockers: some calcium channel antagonists (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.

Cyclosporin: 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, 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. With the simultaneous use of fluconazole and cyclosporine, it is recommended to monitor the concentration of cyclosporine in the blood.

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.

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.

Halofantrine: fluconazole can increase the concentration of halophanthin in the blood plasma in connection with the inhibition of the isoenzyme CYP3A4. The development of arrhythmia of the ventricular tachysystolic type "pirouette" (torsade de pointes) with simultaneous application with fluconazole, as well as with other azole agents, and their joint application is not recommended.

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. If simultaneous therapy with these drugs is necessary, 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.

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): C_maxand the AUC of flurbiprofen increased by 23% and 81%, respectively. Similarly, C_max and the AUC of the pharmacologically active isomer [S - (+) - ibuprofen] increased by 15% and 82%, respectively, with simultaneous application of fluconazole with racemic ibuprofen (400 mg). With the simultaneous use of fluconazole at a dose of 200 mg / day and celecoxib in a dose of 200 mg C_max and AUC of celecoxib increased by 68% and 134%, respectively. In this combination, a dose reduction of celecoxib can be halved.

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 contraceptives: with simultaneous application of combined oral contraceptive with fluconazole at a dose of 50 mg, there is no significant effect on hormone levels, whereas with daily administration 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 1 time per week, the AUC of ethinylestradiol 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.

Phenytoin: simultaneous application of fluconazole and phenytoin may be accompanied by a clinically significant increase in the concentration of phenytoin. If simultaneous use of both drugs is necessary, the concentration of phenytoin should be monitored and its dose adjusted accordingly in order to provide a therapeutic concentration in the blood plasma.

Prednisone: there is a report on the development of acute adrenal insufficiency in the 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 increase in the metabolism of prednisone.

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

Rifabutin: simultaneous application 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 are described. Patients receiving concurrently rifabutin and fluconazole, must be carefully observed.

Saquinavir: AUC is increased by approximately 50%, C_max - by 55%, saquinavir clearance is reduced 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.

Sulfonylurea preparations: fluconazole with simultaneous reception leads to an increase in T_1/2 oral preparations of sulfonylurea (chlorpropamide, glibenclamide, glipizide and tolbutamide). Patients with diabetes mellitus may be assigned joint use of fluconazole and oral sulfonylureas, but the possibility of developing hypoglycemia should be taken into account, in addition, regular monitoring of blood glucose and, if necessary, dosage adjustment of sulfonylureas.

Tacrolimus: single-dose application of fluconazole and tacrolimus (inward) leads to an increase in serum concentrations of the latter up to 5 times by inhibiting the metabolism of tacrolimus occurring in the intestine via the CYP3A4 isoenzyme. Significant changes in the pharmacokinetics of drugs have not been observed with tacrolimus intravenously. Cases of nephrotoxicity are described. Patients who simultaneously take 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.

Theophylline: while simultaneous application with fluconazole at a dose of 200 mg for 14 days, the average plasma clearance rate of theophylline is reduced by 18%. In the administration of fluconazole to patients receiving theophylline in high doses, or patients with an increased risk of toxic theophylline, one should observe the symptoms of theophylline overdose and, if necessary, adjust the therapy accordingly.

Tofacitinib: the exposure of tofacitinib increases with its combined use 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.

Vinca alkaloid: 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.

Vitamin A: There is a report of one case of adverse reactions in the CNS as pseudotumor brain while applying all-trans retinoic acid and fluconazole, which disappeared after withdrawal of fluconazole. The use of this combination is possible, but one should remember about the possibility of undesirable reactions from the CNS.

Zidovudine: the simultaneous use with fluconazole marked increase in C_max and zidovudine AUC by 84% and 74% respectively. This effect is probably due to a decrease in the metabolism of the latter to its main metabolite. Before and after treatment with fluconazole at a dose of 200 mg / day for 15 days, AIDS patients and ARC (AIDS-related complex) had a significant increase in AZOD (20%).

Patients receiving this combination should be observed to identify side effects of zidovudine. Voriconazole (CYP2C9 CYP2C19 inhibitor izosermentov and CYP3A41:. Concurrent voriconazole (400 mg, 2 times a day on the first day followed by 200 mg 2 times a day for 2.5 days) and fluconazole (400 mg on the first day, followed by 200 mg a day for 4 days) increases 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.

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.

The above interaction was established with repeated application of fluconazole; interactions with drugs as a result of a single dose of fluconazole are unknown.

Doctors should take into account that interaction with other drugs has not been specifically studied, but it is possible.

Special instructions:

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

Treatment can be started in the absence of seeding results or other laboratory tests, but if appropriate, appropriate correction of antifungal therapy is recommended.

In the course of treatment, it is necessary to monitor blood counts, kidney and liver function. It is necessary to control the prothrombin index while using the coumarinic anticoagulants simultaneously. If there are violations of kidney and liver function, stop taking the drug.

In rare cases, the use of fluconazole was accompanied by toxic changes in the liver. 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 cases where a 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.

It is recommended to monitor the concentration of cyclosporine in the blood in patients receiving fluconazole, t. in patients with kidney transplantation, fluconazole administration at a dose of 200 mg / day leads to a slow increase in the concentration of cyclosporine in the plasma.

Care should be taken when taking fluconazole simultaneously with cisapride, rifabutin, or other drugs metabolized by the cytochrome P450 system.

Effect on the ability to drive transp. cf. and fur:The experience with fluconazole indicates that it is unlikely that the ability to drive and drive the drug is impaired.

Form release / dosage:Tablets 50 mg, 150 mg.

Packaging:1 tablet (150 mg) or 7 tablets (50 mg) in a PVC / aluminum blister. One blister along with instructions for use are packed in a cardboard pack.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep the medicinal product in its secondary packaging.

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:Without recipe

Registration number:П N014389 / 01

Date of registration:18.09.2009 / 26.10.2015

Expiration Date:Unlimited

The owner of the registration certificate:Dr. Reddy's Laboratories Ltd.Dr. Reddy's Laboratories Ltd. India

Manufacturer: & nbsp

DR. REDDY`S LABORATORIES, LTD. India

Representation: & nbspDR REDDY'S LABORATORIS LTD. DR REDDY'S LABORATORIS LTD. India

Information update date: & nbsp08.06.2018

Illustrated instructions

Instructions

Mycoflucan® (Mycoflucan)