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

Excipients: lactose (milk sugar) 131.0 mg, 81.0 mg, 31.0 mg; corn starch 12.0 mg, 12.0 mg, 12.0 mg; povidone (polyvinylpyrrolidone) 5.0 mg, 5.0 mg, 5.0 mg; silicon dioxide colloid (aerosil) 1.0 mg, 1.0 mg, 1.0 mg; magnesium stearate 1.0 mg, 1.0 mg, 1.0 mg.

Description:

Hard gelatin capsules # 1 of orange color for a dosage of 50 mg; white for a dosage of 100 mg and yellow for a dosage of 150 mg. The contents of the capsules are a powder or granules of 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:

Fluconazole, a representative of the class of triazole antifungal agents, is a potent selective inhibitor of the synthesis of sterols in the fungal cell.

The drug is effective in opportunistic mycoses, including those caused by Candida spp., Cryptococcus neoformans, Microsporum spp., Trichophyton spp. Also shown is the activity of fluconazole in endemic mycosis models, including infections caused by Blastomyces dermatitidis, Coccidiodes immitis and Histoplasma capsulatum.

Pharmacokinetics:

after oral administration, 150 mg on an empty stomach is 90% of the plasma content when given intravenously at a dose of 2.5 to 3.5 mg / l. Simultaneous food intake does not affect the absorption of the drug taken internally. The concentration in the plasma reaches a peak 0.5-1.5 h after administration, the half-life (T1 / 2) of fluconazole is about 30 h. The plasma concentrations are in direct proportion to the dose.90% level of equilibrium concentration is reached by 4-5 days of treatment with the drug (with the administration of 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 level corresponding to 90% of the equilibrium concentration by the second day. The apparent volume of distribution approximates the total water content in the body. Binding to plasma proteins - 11-12%. It is an inhibitor of the isoenzyme CYP2C9 in the liver.

Fluconazole well penetrates into all body fluids. The concentrations of fluconazole in saliva and sputum are similar to those in plasma. In patients with fungal meningitis, the fluconazole content in the cerebrospinal fluid reaches 80% of its concentration in the plasma.

In the stratum corneum, the epidermis, the dermis and the sweat fluid, high concentrations are reached that exceed the serum levels.

Fluconazole is excreted mainly by the kidneys; approximately 80% of the administered dose is excreted in the urine unchanged. Metabolites of fluconazole in peripheral blood were not detected. The pharmacokinetics of fluconazole significantly depends on the functional state of the kidneys, and there is an inverse relationship between T1 / 2 and creatinine clearance. After hemodialysis for 3 hours the concentration of fluconazole in plasma is reduced by 50%.

Indications:

Treatment

- cryptococcosis, including cryptococcal meningitis and other localizations of this infection (including lungs, skin), both in patients with normal immune response, and in patients with various forms of immunosuppression (including AIDS patients, organ transplantation);

general candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidiasis infections (infections of the abdominal, endocardial, eye, respiratory and urinary tract), including in patients with malignant tumors in intensive care units receiving cytotoxic or immunosuppressive agents , as well as in patients with other factors predisposing to the development of candidiasis; .

Candidiasis of the mucous membranes, including oral and pharyngeal cavities (including atrophic candidiasis of the oral cavity associated with wearing dentures), esophagus, non-invasive bronchopulmonary candidiasis, candiduria, candidiasis of the skin;

genital candidiasis: vaginal candidiasis (acute and chronic recurrent), candida balanitis;

mycosis of the skin, including mycosis of the feet, the body, the groin area; offshoot lichen,

onychomycosis; candidiasis of the skin; ’ , '

Deep endemic mycoses, including coccidiomycosis, paracoccidiomycosis,

sporotrichosis and histoplasmosis in patients with normal immunity. '

Prevention,

cryptococcal infection in AIDS patients;

fungal infections in patients with malignant tumors, predisposed to, such infections due to cytotoxic chemotherapy or radiation therapy;

relapse of oropharyngeal candidiasis in AIDS patients;

recurrences of vaginal candidiasis (3 or more episodes per year).

Contraindications:

simultaneous reception. Terfenadine or astemizole and other drugs that extend the Q-T interval;
increased sensitivity to fluconazole or a close structure of azole compounds;
pregnancy, lactation period, children's age up to 3 years (for this dosage form);
deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

Carefully:

Hepatic insufficiency, 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 flucoazole at a dose of 400 mg / day,potentially 'proaritmogenic states - in patients with multiple risk factors (organic heart disease, electrolyte balance disorders, simultaneous reception of funds causing arrhythmias).'

Pregnancy and lactation:

, The drug is contraindicated in pregnancy.

Women of childbearing age should use contraception. Fluconazole is found in breast milk in concentrations; close to plasma, so if you need to use the drug during lactation, you should decide whether to stop breastfeeding.

Dosing and Administration:

, Inside.

In adults with cryptococcal meningitis and cryptococcal infections, other localizations on the first day, 400 mg are 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 at least 6-8 weeks.

To prevent the recurrence of cryptococcal meningitis in AIDS patients, after completion of the full course of primary treatment, fluconazole prescribe at a dose of 200 mg / day for a long period of time.

With candidemia, disseminated candidiasis and other invasive, candidiasis infections, the dose is usually 400 mg on the first day, and then at 200 mg. With insufficient clinical efficacy, the dose of the drug may be increased

up to 400 mg / day. The duration of therapy depends on clinical effectiveness.

"With oropharyngeal candidiasis, the drug is usually prescribed at 50-100 mg 1 time / day; the duration of treatment is 7-14 days. If necessary, in patients with a marked decrease in immunity, treatment may be longer.

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

With other localizations of candidiasis (with the exception of genital candidiasis), for example, with esophagitis, noninvasive bronchopulmonary disease, candiduria, candidiasis of the skin and mucous membranes, etc., the effective dose usually amounts to - 50-100 mg / day with the duration of treatment 14-30 days: To prevent the recurrence of oropharyngeal candidiasis in AIDS patients after completion of the full course of primary therapy, the drug can be administered at 150 mg once a week.

With vaginal candidiasis fluconazole taken once in 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 once a month. The duration of therapy is determined individually; it varies from 4 to 12 months. Some patients may need more frequent use.

With balanitis caused by Candida, fluconazole appoint single dose in a dose of 150 mg 'inside.

For the prevention of candidiasis, the recommended dose of fluconazole is 50-400 mg 1 time / 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 1 time / day. Fluconazole appoint a few days before the expected appearance of neutropenia; after an increase in the number of neutrophils

more than 1000 / mm treatment is continued for another 7 days.

With mycosis of the skin, including mycosis of the feet, skin of the inguinal area, and skin candidiasis, the recommended dose is 150 mg once a week or 50 mg 1 time / day. Duration of therapy in usual cases is 2-4 weeks, however, with foot mycoses, longer therapy (up to 6 weeks) may be required.With pityriasis 300 mg once a week for 2 weeks, some patients require a third dose of 300 mg per week, whereas in some cases / is sufficient to receive 300-400 mg once; an alternative treatment regimen is to apply 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). To re-grow the nails on the fingers and toes, it normally takes 3-6 months and 6-12 months, respectively. With deep endemic mycoses, it may be necessary to use 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 11-24 months with coccidiomycosis, 2-17 months with paracoccidiomycosis, 1-16 months with sporotrichosis and 3-17 months with histoplasmosis."

In 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 in adults / The drug is used daily 1 time / day.

Candidiasis of the mucous membranes. the recommended dose of fluconazole is 3 mg / kg / day.On the first day, a "shock" dose of 6 mg / kg may be prescribed to achieve a more rapid equilibrium equilibrium concentration. ' ,

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

For the prevention of fungal infections in children with reduced immunity, the risk of developing infections associated with neutropenia, resulting from cytotoxic chemotherapy or radiotherapy, is prescribed at 3-12 mg / kg / day, depending on the severity and duration of preservation of the 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), according to the degree of renal insufficiency.

In elderly patients in the absence of violations of kidney function should follow the usual dosage regimen. Patients with renal failure (creatinine clearance less than 50 mL / min) dosing regimen should be adjusted as indicated below.

Use of the drug in patients with impaired renal function. ' . .

Fluconazole is excreted mainly with urine in unchanged form. With a single admission, a dose change is not required. When the drug is used again, patients with impaired renal function should first enter a "shock" dose of 50 mg to 400 mg. If the clearance of creatinine (CC) is more than 50 ml / min, the usual dose of the drug (100% of the recommended dose) is used. With SC from 11 to 50 ml / min, a dose equal to 50% of the recommended dose is used. Patients regularly on dialysis, one dose of the drug'applied after each session of hemodialysis.

From the cardiovascular system, an increase in the duration of the Q-T interval, fibrillation / flutter of the ventricles.

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

Other: impaired renal function, alopecia, hypercholesterolemia,

hypertriglyceridemia, hypokalemia.

Side effects:

From the nervous system: headache, dizziness, convulsions, change in taste.

From the digestive system: abdominal pain, diarrhea, flatulence, nausea, dyspepsia, vomiting, hepatotoxicity (including rare instances fatal), increased levels of alkaline phosphatase, bilirubin, serum aminotransferases (ALT and AST), the liver, hepatitis, hepatocellular necrosis, jaundice.

From the cardiovascular system: an increase in the QT interval on the ECG, fibrillation / flutter of the ventricles.

Dermatological reactions: rash, alopecia, exfoliative skin diseases including Stevens-Johnson syndrome and toxic epidermal necrolysis.

On the part of the hematopoiesis system: leukopenia, including neutropenia and agranulocytosis, thrombocytopenia.

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

Allergic reactions: anaphylactic reactions (including angioedema, edema of the face, urticaria, pruritus).

Overdose:

Symptoms: hallucinations, paranoid behavior.

Treatment: symptomatic, gastric lavage, forced - diuresis.,

Hemodialysis within 3 hours reduces the plasma concentration by approximately 50%.

Interaction:

When used simultaneously with warfarin fluconazole increases prothrombin time (by 12%), which is why bleeding can develop (hematomas, nosebleeds and digestive tract, hematuria, melena). Patients receiving coumarin anticoagulants should constantly monitor prothrombin time.

After ingestion of midazolam fluconazole significantly increases the concentration of midazolam and psychomotor effects, and this effect is more pronounced after taking fluconazole inward than when it is used iv. If concomitant therapy with benzodiazepines is required in patients taking fluconazole, should be observed with a view to a corresponding reduction in the dose of benzodiazepine.

With the simultaneous use of fluconazole and cisapride, unwanted reactions from the heart are possible, incl. fibrillation / flutter of the ventricles (arrhythmia of the "pirouette" type). The use of fluconazole at a dose of 200 mg 1 time / day and cisapride in a dose of 20 mg 4 times / day leads to a pronounced increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG. Simultaneous administration of cisapride and fluconazole is contraindicated.

In patients after kidney transplantation, 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.

Multiple application of hydrochlorothiazide simultaneously with fluconazole leads to an increase in the concentration of fluconazole in 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 this should be taken into account.

With simultaneous application of 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 of fluconazole, the AUC of ethinylestradiol and levonorgestrel increase by 40% and 24% respectively, and with 300 mg of fluconazole 1 time week - AUC of ethinylestradiol and norethindrone increase by 24% and 13%, respectively. Thus, the repeated use of fluconazole at these doses is unlikely to affect the effectiveness of combined oral contraceptives.

The simultaneous use of fluconazole and phenytoin may be accompanied by a clinically significant increase in the concentration of phenytoin. With this combination, the concentration of phenytoin should be monitored and its dose adjusted accordingly to ensure therapeutic serum concentration.

The simultaneous use of fluconazole and rifabutin may lead to an increase in serum concentrations of the latter. With the simultaneous use of fluconazole and rifabutin, cases of uveitis are described. Patients receiving concurrently rifabutin and fluconazole, must be carefully observed.

Simultaneous application of fluconazole and rifampicin results in AUC decrease by 25% and duration of T_1/2 fluconazole by 20%. In patients who simultaneously take rifampicin, it is necessary to consider the advisability of increasing the dose of fluconazole.

Fluconazole with simultaneous reception leads to an increase in T_1/2 oral preparations of sulfonylurea (chlorpropamide, glibenclamide, glipizide and tolbutamide). Patients with diabetes can be appointed together fluconazole and oral sulfonylurea preparations,but the possibility of developing hypoglycemia should be taken into account.

Simultaneous application of fluconazole and tacrolimus leads to an increase in plasma concentrations of the latter. Cases of nephrotoxicity are described. With this combination, patients should be closely monitored.

With the simultaneous use of azole antifungal agents and terfenadine, serious arrhythmias can occur as a result of an increase in the QT interval. When fluconazole was taken at a dose of 200 mg / day, there was no increase in the QT interval, however, the use of fluconazole at doses of 400 mg / day and above caused a significant increase in the concentration of terfenadine in plasma. Simultaneous administration of fluconazole in doses of 400 mg / day or more with terfenadine is contraindicated. Treatment with fluconazole in doses less than 400 mg / day in combination with terfenadine should be carefully monitored.

With 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 developing toxic theophylline, one should observe the appearancesymptoms of an overdose of theophylline and, if necessary, adjust the therapy accordingly.

With simultaneous use with fluconazole, there is an increase in zidovudine concentrations, which 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%).

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 intervals of 21 days between the two schemes, a significant increase in zidovudine AUC (74%) was observed with simultaneous application with fluconazole. Patients receiving this combination should be observed to identify side effects of zidovudine.

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. With such combinations, patients should be closely monitored.

Special instructions:

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 was no apparent dependence on 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. When there are clinical signs of liver damage that may be associated with fluconazole, the drug should be withdrawn. Patients with AIDS are more likely to develop severe skin reactions when using many drugs. In those cases when a rash develops in patients with superficial fungal infection and it is regarded as definitely associated with fluconazole, the drug should be withdrawn. When rashes appear in patients with invasive / systemic fungal infections, they should be carefully monitored and the fluconazole taken off when bullous changes or erythema multiforme occur. - *

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:

When taking fluconazole, side effects (headache / dizziness, convulsions) may develop, so care should be taken when driving and doing work that requires increased concentration.

Form release / dosage:Capsules 50 mg, 100 mg, 150 mg

Packaging:

For 1 or 10 capsules with a dosage of 150 mg, for 2 or 10 capsules with a dosage of 100 mg and -, for 4, 7 or 10 capsules with a dosage of 50 mg per circuit cell pack or a can of polymer.

1 a contoured cell pack or jar, together with an instruction for use, is placed in a pack.

A polymer-free can is supplied with a glue instruction for use and placed in a group package.

Storage conditions:

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

Shelf life:

2 years. Do not use after the expiration date.

Terms of leave from pharmacies:Without recipe

Registration number:LS-001339

Date of registration:28.09.2011

The owner of the registration certificate:PHARMACY 36.6, CJSC PHARMACY 36.6, CJSC Russia

Manufacturer: & nbsp

VEROPHARM SA Russia

Information update date: & nbsp28.09.2015

Illustrated instructions

Instructions

Fluconazole (Fluconazole)