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

50 mg: Active substance: fluconazole 50 mg;, auxiliary substances: corn starch - 5 mg, silicon dioxide colloid -1 mg, magnesium stearate - 1 mg, microcrystalline cellulose - 43 mg; capsule hard gelatinous white color Ns 3: gelatin-up to 100%, titanium dioxide [E171] -2.0%.

150 mg: Active substance: fluconazole * 150 mg; auxiliary substances: corn starch -15 mg, silicon colloidal dioxide-3 mg, magnesium stearate-3 mg, cellulose, - microcrystalline-129 mg; capsule hard gelatinous yellow Ns 0: gelatin - up to 100%, titanium dioxide [E171] - 1.3333%, dye quinoline yellow [E104] -0.9197%, dye sunset yellow [E110] -0.0044%. , , . .

Description:

Dosage 50 mg: capsules of hard gelatinous white No. 3. The contents of the capsules are a white or white powder with a yellowish hue.

Dosage of 150 mg: capsules of hard gelatinous No. 0 yellow. Contents of capsules .. - powder white or white with a yellowish hue.

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 action, inhibiting! activity of the fungal dependent components of cytochrome P450. It blocks the transformation of: lanosterol cells * fungi into 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 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 meningitis and encephalitis), Microsporam spp., And Trichophyton spp., With endemic mycoses caused by Blastomyces dermatidis and Histoplasma capsulatum with normal or suppressed immunity.

Pharmacokinetics:

After oral administration fluconazole well absorbed, food intake does not affect the rate of absorption of fluconazole, its bioavailability is 90%.

Time of maximum concentration (Stach) after ingestion; fasting 150 mg

0.5-1.5 hours and is 90% of the concentration. in plasma with intravenous administration in a dose of 2.5-3.5 mg / l. The half-life of the fluconazole is approximately 30 hours. The connection with plasma proteins is 11-12%. The concentration in the plasma is in the direct

dose dependence. 90% the level of equilibrium concentration is reached, by the 4th-5th day of treatment with the drug (when taken once a day). '

The application on the first day of a dose, 2 times greater than the usual daily dose /

: allows to achieve a level of fluconazole concentration in plasma corresponding to 90%, equilibrium concentration, 'to the second day.

- 'Fluconazole' is good-penetrating! all biological fluids of the body.

The concentration of the active substance of the drug in breast, milk, articular fluid ;,

; saliva, sputum and peritoneal fluid is analogous to that in the plasmic-tissue. Constant values in the vaginal secretion are achieved 8 hours after taking>

'Inside and held at this level for at least 24 hours. Fluconazole well penetrates into the cerebrospinal fluid (CSF), with fungal meningitis concentration in the CSF '.

, is about 80% of its plasma level. In the sweat fluid, the epidermis and in. ; horn layer (selective accumulation), concentrations greater than

whey

After oral administration of 150 mg on day 17, the concentration in the stratum corneum of the dermis is 23.4 μg / g, and 1 week after the second dose, 7.1 μg / g; concentration in the nails after 4 months: 150 mg once a week - 4.05 μg / g in healthy and 1.8 μg / g in affected nails. The apparent volume of distribution approximates the total water content in the body.

. Less than 5% of fluconazole is metabolized at the first pass through the liver. , Fluconazole is excreted mainly by the kidneys (80% - unchanged, 11% - in the form of metabolites). Ground clearance. fluconazole s is proportional to the clearance of creatinine. - - - Metabolites of fluconazole in peripheral blood were not detected.

The pharmacokinetics of fluconazole significantly depend on the functional state of the kidneys, and there is an inverse relationship between the half-life and creatinine clearance. After hemodialysis, the concentration of fluconazole in the blood plasma decreases by 50% after 3 hours.

Indications:

, - cryptococcosis, including cryptococcal meningitis and other localizations given

. infections (including lungs, skin), both in patients with normal immune response, and in patients with various forms of immunodepression (including those with AIDS, during organ transplantation); the drug can be used, for - prevention of cryptococcal infection in AIDS patients; -. / ,

, - generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidiasis infections (peritoneal, endocardial, eye, respiratory and urinary tract infections). Treatment can be conducted in patients with malignant neoplasms,intensive care patients, patients undergoing a course of cytostatic or immunosuppressive therapy, and, ■ the presence of other factors predisposing to candidiasis;

- candidiasis mucous membranes, including the mouth and pharynx (including 'atrophic oral candidiasis associated with wearing dentures), esophagus, non-invasive bronchopulmonary candidiasis, candiduria, candidiasis of the skin;

prevention of recurrence of oropharyngeal candidiasis in AIDS patients; *

genital candidiasis: vaginal 'candidiasis (acute and chronic

recurrent), prophylactic use to reduce the frequency of relapses vaginal candidiasis (3 or more episodes a year); Candidiasis balanitis;

'profsaaktika fungal infections ■' in patients with, malignant

neoplasms that are predisposed to: such infections in, as a result of chemotherapy with cytostatics or radiation therapy; . ^ .

mycosis of the skin, including mycoses of the pap, torso, inguinal region; pungent

(colorful) lichen, onychomycosis, skin candidiasis; - . . .

deep endemic mycoses, including coccidioidomycosis and gystoplazmoz in patients with normal immune systems.

Contraindications:

- Hypersensitivity to the drug (including other azole anti-,

, fungal medicinal products in history);

'- simultaneous reception of terfenadine (against the background of a constant intake of fluconazole at a dose of' 400 mg / day or more), cisapride or astemizole and other drugs that extend the QT interval ;,

-baby age up to 3 years

Carefully:

hepatic and / or renal failure, the appearance of a rash on

the background of the use of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections, the simultaneous administration of potentially hepatotoxic drugs, potentially proarrhythmogenic conditions in patients with multiple risk factors (organic heart diseases, electrolyte balance disorders, simultaneous administration medicines,

"causing arrhythmias), simultaneous reception of terfenadine and fluconazole in a dose of less than 400 mg / day, patients with intolerance to acetylsalicylic acid, pregnancy, alcoholism.

Pregnancy and lactation:

"The use of the drug in pregnant women - is inappropriate, with the exception of severe or life-threatening forms of fungal infections, when,the potential benefit of, the use of fluconazole for the mother significantly exceeds the possible risk to the fetus. Fluconazole penetrates into breast milk in a concentration close to the plasma / therefore, the use of the drug during lactation is contraindicated.

Dosing and Administration:

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

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

In cryptococcal meningitis and cryptococcal infections of other locations, 400 mg (8 capsules 50 mg) are usually prescribed on the first day, and then continue treatment at a dose of 200 mg (4 capsules 50 mg) - 400 mg (8 capsules 50 mg) 1 time per day. The duration of treatment for cryptococcal infections depends on the clinical efficacy, confirmed by mycological examination; when cryptococcal meningitis treatment course should be at least 6-8 weeks. In cases of treatment of life-threatening infections, the daily dose can be increased to 800 mg. To prevent the recurrence of cryptococcal meningitis in AIDS patients, after completion of the full course of primary therapy, fluconazole prescribe a dose of 200 mg per day for a long period of time.

With candidemia, disseminated candidiasis and other invasive candidiasis infections, the saturating dose is 800 mg on the first day, the subsequent dose of 400 mg per day. The duration of therapy depends on clinical effectiveness. The general recommendation for the duration of treatment of candidemia is 2 weeks after the first negative result of blood culture and the disappearance of signs and symptoms of candidemia.

With oropharyngeal candidiasis, the saturating dose is 200-400 mg on the first day, the subsequent dose of 100-200 mg once a day for 7-21 days. If necessary, treatment with a pronounced suppression of immune function treatment can be continued for a longer time. To prevent the recurrence of oropharyngeal candidiasis in HIV-infected patients with a high risk of recurrence fluconazole apply 100-200 mg per day or 200 mg 3 times a week for an indefinite period of time in patients with chronically reduced immunity.

With atrophic candidiasis of the oral cavity associated with the wearing of dentures - 50 mg once a day for 14 days in combination with local antiseptic medicines for the treatment of the prosthesis.

With candiduria, the effective dose is usually 200-400 mg / day with the duration of treatment 7-21 days. In patients with severe impairment of the immune system function, longer periods of therapy can be used.

In chronic skin-mucous candidiasis, 50-100 mg per day is used up to 28 days of treatment. Depending on the severity of the treatment of the infection or the concomitant damage to the immune system and infection, longer periods of therapy can be used.

When candidiasis of the esophagus saturating dose is 200 ^ 400 mg on the first day, the subsequent dose of 100-200 mg per day. The course of treatment is 14-30 days (until the remission of candidiasis of the esophagus). If necessary, treatment with a pronounced suppression of immune function treatment can be continued for a longer time. To prevent the recurrence of esophageal candidiasis in HIV-infected patients with a high risk of recurrence fluconazole apply 100-200 mg per day or 200 mg 3 times a week for an indefinite period of time in patients with chronically reduced immunity.

With acute vaginal candidiasis, candida balanitis fluconazole apply once inside at a dose of 150 mg.To reduce the frequency of recurrences of vaginal candidiasis, the drug can be used at a dose of 150 mg every three days - only 3 doses (on days 1, 4 and 7), then maintaining a dose of 150 mg once a week. The maintenance dose can be used up to 6 months.

For the prevention of candidiasis, the recommended dose is 50-400 mg once a day, depending on the degree of risk of fungal infection.

For the prevention of candidiasis in patients with malignant tumors, the recommended dose of fluconazole is 200-400 mg once a day, depending on the degree of risk of fungal infection. If there is a high risk of generalized infection, for example, in patients with expected severe or persistent neutropenia, the recommended dose is 400 mg / day. Fluconazole appoint a few days before the expected appearance of neutropenia. After an increase in the number of neutrophils more than 1 thousand / μl, the treatment is continued for another 7 days.

In case of gait infections, including foot dermatophytosis, trunk trombophlebitis, inguinal dermatophytosis and candidiasis infections, the recommended dose is 150 mg once a week or 50 mg once a day, the dosing regimen depends on the clinical and mycological effect.Duration of therapy in usual cases is 2-4 weeks, however, with foot mycoses, longer therapy (up to 6 weeks) may be required.

With multi-colored lichen, the recommended dose is 300-400 mg once a week for 1-3 weeks. An alternative treatment regimen is the use of the drug at 50 mg once a day for 2-4 weeks.

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 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. After successful treatment of long-lasting chronic infections, the shape of the nails is sometimes observed.

With deep endemic mycoses, it may be necessary to use the drug at a dose of 200-400 mg per day for up to 2 years. For some infections, especially with damage to the meninges, a dose of 800 mg per day can be considered. The duration of therapy is determined individually: it can be 11-24 months with coccidioidomycosis and 3-17 months with histoplasmosis.

Use in children

In children, as with similar infections in adults, the duration of treatment depends on the clinical and mycological effect. The drug is used daily once a day, the maximum daily dose is 12 mg / kg.

In candidiasis of mucous membranes, the recommended dose of fluconazole is 3 mg / kg per day. On the first day, a shock dose of 6 mg / kg can be administered to achieve equilibrium concentrations more quickly.

For treatment of generalized candidiasis or in cryptococcal infection, the recommended dose is 6-12 mg / kg per day, depending on the severity of the disease.

For the prevention of fungal infections in children with reduced immunity, where the risk of infection is associated with neutropenia developing as a result of cytotoxic chemotherapy or radiation therapy, the drug is prescribed at 3-12 mg / kg per day, depending on the severity and duration of preservation of induced neutropenia .

To suppress recurrence of cryptococcal meningitis in children with AIDS, the recommended dose of fluconazole is 6 mg / kg per day.

Use in elderly patients

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

Use in patients with renal insufficiency

With a single admission dose changes are not required. Patients (including children) with impaired renal function after repeated use of the drug should initially enter a loading dose of 50 mg to 400 mg, followed by a daily dose (depending on indication) is set according to the following table:

Creatinine clearance (ml / min)

Percent recommended dose

>50

<50 (without dialysis) Routine dialysis

100%

50%

100% after each dialysis

Side effects:

From the digestive system: loss of appetite, change in taste, abdominal pain, nausea, vomiting, diarrhea, flatulence, abdominal pain, impaired pecheni- function (jaundice, hepatitis, gepatonekroz 'giperbilirubinemyya; increasing activity of alanine aminotransferase (ALT), aspartate aminotransferase' (ACT), increased activity of alkaline phosphatase (APF), hepatocellular necrosis), in that. number with a fatal outcome.

From the 'side of the nervous' system: the head; pain, dizziness, excessive fatigue, cramps. '

'On the part of the hemopoiesis: leukopenia, thrombocytopenia

(bleeding, petechia), neutropenia, agranulocytosis .., ' . .

From the cardiovascular system: an increase in the duration of the QT interval, flicker / flutter of the ventricles. Allergic reactions: skin rash, multiforme exudative erythema (including Stevens-Johnson syndrome), toxic '' epidermal necrolysis (Lyell's syndrome), anaphylactoid reactions (including angioedema, facial edema, urticaria, skin itching).

- Other: impaired function of the kidneys, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia .. ' ' , �? -

Overdose:

Overdose - '

Symptoms: hallucinations, paranoid behavior, convulsions.

Treatment: symptomatic, gastric lavage, forced diuresis. Hemodialysis within 3 hours reduces the plasma concentration 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) with simultaneous administration.

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

Cisapride: with the simultaneous use of fluconazole and cisapride, unwanted reactions from the heart are possible, including arrhythmia of the ventricular tachysit-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 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, the increase in the QT interval is not established, however, the use of fluconazole at doses of 400 mg / day above causes a significant increase in the concentration of terfenadine in the blood plasma. the administration of fluconazole 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 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 lengtheningQT interval and in some cases to the development of torsade de pointes ventricular arrhythmia of tachysystolic type. Simultaneous use of astemizole and fluconazole 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 pimozide can lead to an elongation of the QT interval and, in some cases, the development of a torsade de pointes ventricular arrhythmic tachysystolic type. Simultaneous use of pimozide 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 lengthening of the QT interval and in some cases with the development of torsade de pointes (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.

Caution should be exercised and, possibly, dose adjustments should be made when using the following drugs and fluconazole:

Drugs affecting fluconazole: Hydrochlorothiazide: repeated use 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 25% reduction in AUC and a 20% decrease in the half-life of fluconazole. 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 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 a rise 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.

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: increased effect. The concentration of 5-nortryptiline and / or S-amitriptyline can be measured at the beginning of fluconazole and one week after the onset. If necessary, adjust the dose of amitriptyline / nortriptyline.

Amphotericin B: In studies on 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 fumi- gatus. 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%), which is why bleeding may develop (hematomas, nosebleeds and gastrointestinal tract, hematuria, melena). Patients receiving coumarin anticoagulants should constantly monitor prothrombin time. Also, the appropriateness of correcting the dose of warfarin should be evaluated.

Azithromycin: with the simultaneous administration of fluconazole in a single dose of 800 mg with azithromycin in a single dose of 1200 mg, no pronounced pharmacokinetic interaction between the two drugs has 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 fluconazole is ingested than with intravenous administration. If concomitant therapy with benzodiazepines is required, 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%, Stach by 25-50% and half-life by 25-50% due to inhibition of triazolam metabolism. You may need to adjust the dose of triazolam.

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.

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 simultaneous

the use of cyclophosphamide and fluconazole marked 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.

HMG-CoA reductase inhibitors: with simultaneous application of fluconazole with HMG-CoA reductase inhibitors, metabolized with the CYP3A4 isoenzyme (such as, atorvastatin and simvastatin), or CYP2D6 isoenzyme (such as fluvastatin), the risk of myopathy and rhabdomyolysis increases.If it is necessary to simultaneously treat 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 and 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): Stach and AUC of flurbiprofen are increased by 23% and 81%, respectively. Similarly, Stach and AUC of the pharmacologically active isomer [S- (+) - ibuprofen] increased by 15% and 82%, respectively, while fluconazole was simultaneously administered 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, Stach and AUC of celecoxib are 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: simultaneous use of a combined oral contraceptive with fluconazole at a dose of 50 mg does not significantly affect the level of hormones, whereas with a daily intake of 200 mg fluconazole, the AUC of ethinyl estradiol and levonorgestrel are increased by 40% and 24% and when 300 mg of fluconazole is administered once a 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 use 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 to ensure therapeutic serum concentration.

Prednisone: There is a report on the development of acute adrenal insufficiency in the patient after liver transplantation on the background of the cancellation 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 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 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: increase in concentration

sirolimus in the blood plasma, presumably due to the inhibition of sirolimus metabolism 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.

Sulfonylureas: fluconazole, with simultaneous administration, leads to an increase in the half-life of oral sulfonylureas (chlorpropamide, glibenclamide, glipizide, and yes).Patients with diabetes mellitus may be prescribed joint use of fluconazole and oral sulfonylureas, but this should take into account the possibility of developing hypoglycemia, in addition, regular monitoring of blood glucose and, if necessary, dose adjustment of sulfonylureas.

Tacrolimus: simultaneous application of fluconazole and tacrolimus (inward) leads to an increase in serum concentrations of the latter by a factor of 5 by inhibiting the metabolism of tacrolimus occurring in the intestine by means of 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: with simultaneous

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.

Vinca alkaloid: despite the lack of targeted studies, 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 development of undesirable reactions from the central nervous system (CNS) in the form of a pseudotumor of the brain with the simultaneous use of all 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.

Zidovudine: when used concomitantly with fluconazole, there is an increase in Stach and AUC of zidovudine 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, a significant increase in AUC of zidovudine (20%) was found in patients with AIDS and ARC (AIDS-related complex).

When zidovudine was used in HIV-infected patients at a dose of 200 mg every 8 hours for 7 days with or without fluconazole at a dose of 400 mg / day at 21 day intervals between the two regimens, a significant increase in zidovudine AUC (74%) was observed simultaneous application with fluconazole. Patients receiving this combination should be observed to identify side effects of zidovudine.

Voriconazole (inhibitor of isoenzymes CYP2C9, CYP2C19 and CYP3A4): one

the temporary use of voriconazole (400 mg twice 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

Special instructions:

. Treatment should be continued until the appearance / clinico-hematologic remission. Premature termination of treatment leads to relapse.

In rare cases, the use of fluconazole was accompanied by toxic, liver changes, including fatal, mainly in patients with serious concomitant diseases.In the case of hepatotoxic effects associated with fluconazole, there has been no evidence of their dependence on the total daily dose, duration of therapy, sex and age of the patient. Hepatotoxic effect of fluconazole. it was usually reversible; signs of it disappeared after discontinuation - 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 adept at developing advanced skin reactions when using many drugs. cases in which patients with a superficial, fungal infection develop a rash and it is regarded as definitely - associated with fluconazole, the drug should be canceled. When rashes appear in patients with invasive / systemic fungal infections, they should be carefully observed - and canceled fluconazole with the appearance of bullous changes. or multiform erythema

"Allergic reactions are more common in patients with intolerance to acetylsalicylic acid.

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

Does not affect the ability to manage; car and other mechanisms.However, the possibility of dizziness and seizures should be considered. '

Form release / dosage:

Capsules 50 mg and 150 mg.

Packaging:

For 7 capsules of 50 mg or 1 capsule of 150 mg per circuit cell packaging, or in a can of polymer.

For 1, 2 or 4 contour squares, or 1 bank of polymer, together with instructions for use in a pack of cardboard.

Storage conditions:

In a dry place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:Without recipe

Registration number:LP-001477

Date of registration:06.02.2012

The owner of the registration certificate:FARMPROJECT, CJSC FARMPROJECT, CJSC Russia

Manufacturer: & nbsp

FARMPROJECT, CJSC Russia

Representation: & nbspFARM PROJECT CJSC FARM PROJECT CJSC Russia

Information update date: & nbsp27.09.2015

Illustrated instructions

Instructions

Fluconazole (Fluconazole)