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

1 capsule contains: active substance fluconazole 50.00 mg, 100.00 mg or 150.00 mg; auxiliary substances: lactose monohydrate, corn starch, silicon dioxide colloid, sodium lauryl sulfate, magnesium stearate.

Gelatine capsule:

Body: titanium dioxide (E171), diamond blue FCF (E133) (contained only in a dosage of 150 mg), gelatin.

Cover: titanium dioxide (E171), brilliant blue FCF (E133), gelatin.

Description:

Dosage 50 mg: Hard gelatin capsules No. 4 with opaque lid of light blue color and white body.

Dosage of 100 mg: Hard gelatin capsules No. 2 with an opaque dark-lacquered cover and a white body.

Dosage of 150 mg: hard gelatin capsules number 1 with an opaque lid and a casing of light blue color.

Contents of capsules: a homogeneous powder of white or white with a yellowish hue of color.

Pharmacotherapeutic group:Antifungal agent.

ATX: & nbsp

J.02.A.C Triazole derivatives

J.02.A.C.01 Fluconazole

Pharmacodynamics:

Fluconazole is a representative of the class of triazole antifungal agents, it is a highly specific inhibitor of the activity of cytochrome P450-dependent enzymes, including 14-alpha-demethylase, which catalyzes the conversion of lanosterol to ergosterol, which blocks the synthesis of ergosterol, the structure and function of the fungal cell membrane.

Fluconazole has high antifungal activity against Candida albicans and other Candida spp., Cryptococcus spp. 40% Candida glabrata has primary resistance to fluconazole, Candida krusei, Aspergillus spp. and Mucor spp. resistant to fluconazole.

Pharmacokinetics:

The pharmacokinetics of fluconazole when taken orally is similar to pharmacokinetics in intravenous (IV) administration.

Suction

After oral administration fluconazole is well absorbed, its plasma concentration (and total bioavailability) exceeds 90% of plasma fluconazole concentration after intravenous administration. Simultaneous food intake does not affect absorption during ingestion. The maximum concentration (Sta *) is reached in 0,5-1,5 h after administration of fluconazole on an empty stomach. Concentration in plasma is proportional to the dose. When taking the recommended daily dose once a day, the equilibrium concentration (Css) reaches 90% to 4-5th give the drug treatment. The introduction of a shock dose in the first day, which is 2 times higher than the average daily dose, makes it possible to accelerate the achievement of Css equal to 90% by the 2nd day.

Distribution

The apparent volume of distribution approximates the total water content in the body. Binding to proteins is low (11-12%).

Fluconazole well penetrates into many body fluids. The concentration of fluconazole in saliva, sputum, breast milk, articular fluid and peritoneal fluid is similar to its concentration 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.In patients with fungal meningitis, the concentration of fluconazole in the cerebrospinal fluid is about 80% of its plasma concentration. In the stratum corneum of the epidermis, the epidermis-dermis and the sweat fluid, high concentrations are reached that exceed the serum levels. Fluconazole accumulates in the stratum corneum of the epidermis. When administered at a dose of 50 mg once a day, the fluconazole concentration was 73 μg / g after 12 days, and only 5.8 μg / g 7 days after discontinuation of treatment. When applied at a dose of 150 mg 1 time / week, the fluconazole concentration in the stratum corneum on the 7th day was 23.4 μg / g, and 7 days after the second dose, 7.1 μg / g. The concentration of fluconazole in the nail plates after 4 months of use at a dose of 150 mg 1 time / week was 4.05 μg / g in healthy and 1.8 μg / g in the affected nails; 6 months after completion of therapy fluconazole, as before, was determined in the nail plates.

Metabolism and excretion

Fluconazole is excreted mainly by the kidneys; approximately 80% of the administered dose is detected in the urine unchanged. The clearance of fluconazole is proportional to the creatinine clearance. No circulating metabolites were detected.A long half-life (Tu,) from the plasma allows one to take fluconazole once for vaginal candidiasis and 1 time / day or 1 time / week for other indications.

Indications:

Genital candidiasis. Acute or recurrent vaginal candidiasis, if local treatment is not effective.
Candidiasis of the mucous membranes, including mucous membranes of the oral cavity and pharynx, esophagus, noninvasive bronchopulmonary candidiasis, candiduria, mucocutaneous and chronic atrophic candidiasis of the oral cavity (associated with the wearing of dentures with ineffectiveness of local treatment).
Mycosis of the skin, including mycosis of the feet, body, inguinal region, pityriasis, onychomycosis and cutaneous candidiasis infections.
Generalized candidiasis, including candidemia, disseminated candidiasis and other invasive candidiasis infections with lesions of the abdominal cavity, endocardium, eyes, respiratory organs and urogenital organs, incl. in patients receiving cytotoxic or immunosuppressive agents.
Cryptococcal meningitis in patients with normal immune response, patients with an unidentified cause of immunodepression, AIDS patients,recipients of transplanted organs and patients with immunodeficiency caused by other causes; maintenance therapy to prevent recurrence of cryptococcosis in AIDS patients.
Prevention of fungal infections in patients with malignant tumors against cytotoxic chemotherapy or radiotherapy.

Contraindications:

Hypersensitivity to fluconazole, other azole antifungal drugs or to other components of this drug; simultaneous administration of cisapride, terfenadine (against the background of the continuous administration of fluconazole at a dose of 400 mg / day or more), pimozide, astemizole, quinidine; congenital or revealed elongation of QT interval on ECG, simultaneous reception of drugs prolonging QT interval (antiarrhythmics of IA and III classes); hereditary intolerance to galactose, lactase deficiency and glucose-galactose malabsorption syndrome; period of pregnancy; lactation period; children under the age of 16 years.

Carefully:

If there is a violation of the liver function, impaired renal function, predisposition to the development of arrhythmia, electrolyte imbalance (hypokalemia, hypomagnesemia, hypocalcemia), organic heart disease,including cardiomyopathies, severe chronic heart failure, clinically significant bradycardia, arrhythmia, the appearance of rash against the background of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections, concurrent administration of terfenadine and fluconazole at a dose of less than 400 mg / day.

Pregnancy and lactation:

The administration of fluconazole during the first trimester of pregnancy in doses less than 200 mg per day did not lead to an increase in the frequency of fetotoxicity, however, fluconazole has teratogenic effects.

The cases of multiple congenital malformations in newborns whose mothers received fluconazole therapy at high doses (400-800 mg / day) for coccidioidomycosis for 3 or more months were described. The relationship between these disorders and the administration of fluconazole has not been established.

Avoid the use of fluconazole in pregnancy, except in cases of severe and potentially life-threatening mothers of fungal infections, when the expected benefit of treatment for the mother exceeds the possible risk to the fetus. Women of childbearing age should use reliable methods of contraception during treatmentand within 7 days after its termination, and before the appointment of the drug to make sure of the absence of pregnancy.

Fluconazole penetrates into breast milk in concentrations close to plasma. If the drug is necessary, stop breastfeeding before treatment.

Dosing and Administration:

Inside, regardless of food intake.

Capsules should be swallowed whole, with a glass of water.

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

Adults

Vaginal candidiasis: once 150 mg.

Candidiasis of the mucous membranes of the oral cavity and pharynx: 50 mg 1 time / day for 7-14 days. Normally, treatment should not exceed 14 days, except for patients with severe immunity disorders.

Chronic atrophic candidiasis of the oral cavity associated with the wearing of dentures: 50 mg once a day for 14 days in combination with local antiseptics. Other candidal infections of the mucous membranes (with the exception of the above described vaginal candidiasis), for example, with esophagitis, noninvasive bronchopulmonary infections, mucocutaneous candidiasis, etc .: 50 mg per day for 14-30 days.

In severe cases of candidal infections of mucous membranes, in particular with relapses, the daily dose can be increased to 100 mg / day.

Mycosis of the skin, including mycosis of the feet, the body, the groin and skin candidiasis: 150 mg 1 time / 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.

Onychomycosis: 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 usually takes 3-6 and 6-12 months, respectively. However, the growth rate can vary widely between different people, as well as in

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

Shingles: 300 mg 1 time / week for 2 weeks; some patients require a third dose of 300 mg / week, while for some patients a single dose of 300-400 mg is sufficient. Alternative scheme of treatment - 50 mg 1 time / day for 2-4 weeks.

Candidemia, disseminated candidiasis and other invasive candidiasis infections: an average of 400 mg in the first day, and then 200 mg / day. Depending on the severity of the clinical effect, the dose can be increased to 400 mg / day. The duration of therapy depends on clinical effectiveness.

Cryptococcal meningitis: on the first day an average of 400 mg, followed by 200-400 mg 1 time / day. The duration of treatment of cryptococcal infections depends on the presence of a clinical and mycological effect, treatment usually lasts no less than 6-8 weeks.

Prevention of recurrence of cryptococcal meningitis in AIDS patients: after completion of the full course of primary treatment with fluconazole at a dose of 200 mg / day can continue for a very long period.

Prophylaxis of candidiasis: 50-400 mg 1 time / day, depending on the degree of risk of developing fungal infection. If there is a high risk of generalized infection, for example, in patients with severe or long-lasting neutropenia after cytotoxic chemotherapy or radiation therapy, the recommended dose is 400 mg 1 time / day. Fluconazole appoint a few days before the expected appearance of neutropenia and after increasing the number of neutrophils more than 1000 / μl, the treatment is continued for another 7 days.

Children over 16 years of age

Dosing and Administration - as with similar infections in adults, the duration of treatment depends on the clinical and mycological effect. The maximum daily dose for children is 400 mg. Fluconazole apply daily 1 time / sut.

Use in children with impaired renal function: see below "Patients with impaired renal function".

Older patents

In the absence of signs of renal failure, the drug is used in a standard dose.

Patents with impaired renal function

Fluconazole is excreted mainly with urine in unchanged form. With a single admission, a dose change is not required. In patients, including children, with renal dysfunction with repeated use of the drug, a "shock" dose of 50 mg to 400 mg should be initially administered, after which the daily dose is determined depending on the indications in the following table.

Creatinine clearance (ml / min)	Percent of Recommended Dose
>50	100%
<50 (without dialysis)	50%
Patients permanently on dialysis	100% after each dialysis session

Side effects:

The most common side effects observed during clinical trials of fluconazole are: headache, skin rash, abdominal pain, diarrhea and nausea.

The incidence of side effects is classified according to the recommendations of the World Health Organization: very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely - less than 0.01%.

From the nervous system: often - headache; infrequently - dizziness, paresthesia, convulsions, seizures, tremor, insomnia, drowsiness.

From the cardiovascular system: rarely - an arrhythmia of the type "pirouette", an extension of the QT interval.

From the digestive system: often - nausea, vomiting, diarrhea, abdominal pain; infrequently - anorexia, constipation, indigestion, flatulence, dryness of the mucous membranes of the oral cavity, a violation of taste.

From the side of the liver and bile-excreting tracts: often a clinically significant increase in the activity of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase; infrequently - cholestasis, hepatitis, jaundice, clinically significant increase in the concentration of total bilirubin in blood plasma (0.3%), hepatocellular necrosis; rarely - hepatic insufficiency, hepatitis.

From the urinary system: rarely - a violation of kidney function.

On the part of the organs of hematopoiesis: infrequently anemia; rarely - leukopenia, thrombocytopenia, neutropenia, agranulocytosis.

On the part of the skin: infrequently - increased sweating, drug dermatitis; rarely - alopecia; very rarely - acute generalized exanthematous pustular rash.

From the side of the organ of hearing and balance: infrequently - vertigo.

From the side of metabolism: rarely - hypokalemia, hypertriglyceridemia, hypercholesterolemia.

From the musculoskeletal system: infrequently - myalgia.

Allergic reactions: often - a rash; rarely - anaphylaxis, multiforme exudative erythema (including Stevens-Johnson syndrome); very rarely - exfoliative dermatitis, toxic epidermal necrolysis (Lyell's syndrome), angioedema, facial edema, urticaria, skin itching.

On the part of the body as a whole: infrequently - general weakness, malaise, fever, increased fatigue.

Children experience side effects more often than adults. The most typical adverse reactions for children are irritability and anemia.

Overdose:

In one of the cases of an overdose of fluconazole in a 42-year-old patient infected with HIV, after taking 8200 mg of fluconazole, hallucinations and paranoid behavior appeared.The patient was hospitalized, his condition returned to normal within 48 hours. Treatment: symptomatic therapy (including maintenance measures and gastric lavage). The three-hour hemodialysis reduces the plasma fluconazole concentration by approximately 50%.

Interaction:

Medicines that are contraindicated in the simultaneous administration of fluconazole With the simultaneous administration of fluconazole and cisapride, cardiac rhythm disturbances occur, including arrhythmia of the "pirouette" type.

With the simultaneous use of fluconazole at a dose of 400 mg / day or more with terfenadine, an increase in the concentration of terfenadine in the blood plasma, which leads to an increased incidence of palpitations, tachycardia, dizziness, chest pain and prolongation of the QTc interval. This effect is absent when using fluconazole at a dose of 200 mg / day. If a simultaneous application of fluconazole and terfenadine is required, the dose of fluconazole should be less than 400 mg / day.

Astemizole in high doses with simultaneous application with fluconazole leads to lengthening of the QT interval, severe ventricular arrhythmias, pirouette arrhythmias and cardiac arrest.

With the simultaneous use of fluconazole and other drugs that increase the QT interval, patients should be closely monitored by the doctor because of the risk of heart rhythm disturbances.

Drugs that alter the metabolism of fluconazole

Multiple application of hydrochlorothiazide simultaneously with fluconazole leads to an increase in the concentration of fluconazole in plasma by 40%. This effect does not require a change in the dosage regimen of fluconazole, but it should be considered.

Simultaneous application of fluconazole and rifampicin leads to a decrease in AUC and b / g fluconazole by 25% and 20%, respectively. In such patients, an increase in the dose of fluconazole is possible.

Medicines, the metabolism of which varies with the administration of fluconazole

Fluconazole inhibits the metabolism of halofantrine.

Fluconazole enhances the effects of methadone. AUC methadone increases with simultaneous application with fluconazole by 35%.

Fluconazole increases the concentration of carbamazepine in blood plasma with simultaneous application.

With simultaneous application with fluconazole AUC fluvastatin increases to 200%.Particular care should be taken when using fluconazole and other inhibitors of the CYP2C9 isoenzyme concurrently with fluvastatin. The use of fluconazole leads to an increase in the concentration of rifabutin in the blood plasma. Patients receiving this combination may develop uveitis. When rifabutin and fluconazole are used concomitantly, patients should be closely monitored.

Fluconazole with simultaneous application with warfarin in men raises prothrombin time by 12%, which is why bleeding may develop (hematomas, nosebleeds and gastrointestinal tract, hematuria, melena). Patients receiving indirect anticoagulants should constantly monitor prothrombin time.

Simultaneous use of fluconazole and phenytoin may be accompanied by a clinically significant increase in the concentration of phenytoin in the blood plasma. In case of simultaneous use of both drugs, the concentration of phenytoin in the blood plasma should be monitored and a corresponding change in the dose of phenytoin should be made. Simultaneous application of fluconazole 400 mg and alfentanil at a dose of 20 μg / kg iv increases the AUC of alfentanil by a factor of 2 and reduces its clearance by 55% due to inhibition of the CYP3A4 isoenzyme.When this combination is used, the dose of alfentanil should be changed.

Induction of short-acting benzodiazepines (midazolam) together with fluconazole leads to an increase in the concentration of midazolam in the blood plasma and an increase in its psychomotor effects, and this effect is more pronounced after taking fluconazole inwards than with its intravenous administration. When fluconazole is used and the need for concomitant therapy with benzodiazepines, their dose should be reduced.

The risk of developing myopathy and rhabdomyolysis increases with simultaneous use of HMG-CoA reductase inhibitors (azole antifungals and statins such as atorvastatin). If simultaneous use of these drugs is necessary, the symptoms of myopathy or rhabdomyolysis (muscle pain, muscle tension or muscle weakness) should be monitored, and the activity of serum creatinophosphinase should be monitored. Therapy with statins should be discontinued with a marked increase in the activity of creatine phosphokinase in the blood serum or in establishing the diagnosis of myopathy or rhabdomyolysis, and also if the development of these complications is suspected.

Fluconazole increases the concentration of trimetrexate in the blood plasma, which leads to bone marrow suppression, impaired liver and kidney function, ulceration of the gastrointestinal tract. If a combination of fluconazole and trimetrexate is vital, then careful monitoring of these patients should be carried out. With simultaneous application with fluconazole, an increase in the concentration of zidovudine is observed, due to the slowing of its metabolism. The use of fluconazole at a dose of 200 mg / day leads to a dose-dependent increase in AZUP of AZT ranging from 20% to 74%.

The use of fluconazole at a dose of 200 mg / day leads to a slow increase in the concentration of cyclosporine in blood plasma in patients after kidney transplantation. Multiple administration of fluconazole at a dose of 100 mg / day does not change the concentration of cyclosporine in blood plasma in patients after bone marrow transplantation. With the simultaneous use of fluconazole and cyclosporine, it is recommended to monitor the concentration of cyclosporine in the blood plasma.

With the cancellation of fluconazole after prolonged therapy simultaneously with prednisone, a careful control of the function of the adrenal glands is necessary.

The simultaneous use of fluconazole in a dose of 100 and 200 mg of tacrolimus and leads to increased serum concentrations of the latter of 1.4 and 3.1 times, respectively. Possible the development of anemia, leukopenia, thrombocytopenia, hypokalemia, diarrhea. Cases of nephrotoxicity are described. Patients simultaneously taking such combinations of drugs should be carefully monitored.

Fluconazole, while the application increases the Ty2 hypoglycemic agents for oral administration - sulfonylureas (chlorpropamide, glibenclamide, tolbutamide and glipizide). Patients with diabetes can be assigned together fluconazole and hypoglycemic agents for oral administration - derivatives of sulfonylureas, but at the same time it is necessary to monitor the concentration of glucose in the blood plasma.

With simultaneous use of combined oral contraceptives with fluconazole at 50 mg is not established substantial change ethinyl estradiol concentration, levonorgestrel and norethisterone in plasma whereas with daily intake of 200 mg fluconazole AUC ethinyl estradiol and levonorgestrel is increased by 40% and 24%, respectively, and at The administration of 300 mg fluconazole 1 time / week AUC of ethinylestradiol and norethisterone increases by 24% and 13%, respectively.Thus, the repeated use of fluconazole at these doses does not significantly affect the effectiveness of combined oral contraceptives. It is possible to increase the concentration of amitriptyline in the blood plasma and the development of toxic effects with simultaneous application with fluconazole. With the simultaneous use of fluconazole and nortriptyline, an active metabolite of amitriptyline, there may be an increase in the concentration of nortriptyline in blood plasma. In connection with the risk of developing toxic effects of amitriptyline, it is recommended to monitor the concentration of amitriptyline in blood plasma and, if necessary, change its dose.

With the simultaneous use of a dose of 200 mg fluconazole, there is a twofold increase in the concentration of celecoxib in the blood plasma. It is assumed that this interaction is associated with inhibition of celecoxib metabolism, in which the CYP2C9 isoenzyme participates. Patients who receive fluconazole, the minimum recommended dose of celecoxib should be used.

Simultaneous application with fluconazole leads to an increase in the concentration of losartan and a decrease in the concentration of its active metabolite in the blood plasma.Patients need constant monitoring of blood pressure.

Fluconazole increases the concentration of theophylline in the blood plasma. In the treatment of fluconazole, patients who theophylline in high doses, in case of symptoms of an overdose of theophylline, correction in the treatment regimen should be made.

Some dihydropyridine blockers of "slow" calcium channels, including nifedipine, isradiline, nicardipine, amlodipine and felodipine, are metabolized with the participation of the CYP3A4 isoenzyme. In the literature, there are reports of the development of severe peripheral edema and / or an increase in serum concentrations of "slow" calcium channel blockers with simultaneous use of itraconazole and felodipine, isradipine or nifedipine. A similar interaction can be observed with fluconazole.

It is assumed that the simultaneous use of didanosine and fluconazole is safe and has little effect on the pharmacokinetics and efficacy of didanosine. but

it is important to monitor the response to fluconazole therapy. It is recommended to revise the dose of fluconazole before using didanosine.

Other interactions

Amphotericin B is an antagonist of azole derivatives.

Taking fluconazole orally with food, cimetidine, antacids or after total body irradiation for the purpose of bone marrow transplantation does not affect the absorption of fluconazole.

Special instructions:

Treatment should continue until the appearance of clinical-mycologic remission. Premature termination of treatment leads to relapse. Treatment can be started in the absence of seeding results and other laboratory tests, but if appropriate, appropriate correction of fungicidal therapy is recommended. In the course of treatment, it is necessary to monitor changes in hematological parameters, liver function, kidney function and other biochemical parameters.

If there are violations of kidney and liver function, stop taking the drug.

In very rare cases in patients with severe concomitant diseases who received fluconazole treatment with multiple doses, autopsy revealed changes indicative of liver necrosis. These patients simultaneously received a large number of drugs, some of which have a hepatotoxic potential,and / or had concomitant diseases that could be the cause of liver necrosis. In cases of hepatotoxicity, there was no clear correlation between the total daily dose of fluconazole, duration of therapy, sex or age; After discontinuing fluconazole therapy, the changes were usually reversible.

Effect of fluconazole on the inhibition of cytochrome P450 isoenzymes. including isoenzyme CYP2C9, can persist for 4-5 days after the end of treatment due to prolonged T1 / 2 fluconazole.

For AIDS patients, there is a greater risk of developing serious skin reactions with fluconazole. If a patient who is receiving treatment for an invasive / systemic fungal infection develops a rash that is associated with fluconazole, which has the nature of bullous lesions and multiforme exudative erythema, the drug should be discontinued.

In patients with multiple risk factors, such as organic myocardial changes, water-electrolyte balance disorders, treatment should be performed under the supervision of a physician and accompanied by ECG monitoring.

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

Fluconazole does not affect the ability to drive and work with machinery. However, the possibility of dizziness and seizures should be considered.

Form release / dosage:

Capsules 50 mg, 100 mg, 150 mg.

Packaging:

Dosage of 50 mg: 7 capsules in aluminum foil blisters / PVC / PVDC; 1 blister with instructions for use in a cardboard bundle.

Dosage of 100 mg: 7 capsules in aluminum foil blisters / PVC / PVDC; 1 blister with instructions for use in a cardboard pack; 10 capsules in aluminum foil / PVC / PVDC bottles, 1, 3, 6 or 10 blisters with instructions for use in a cardboard pack.

Dosage of 150 mg: 1 capsule in aluminum foil blisters / PVC / PVDC, 1 blister with instructions for use in a cardboard bundle.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

5 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LSR-007812/10

Date of registration:09.08.2010

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

TEVA Pharmaceutical Works Private, Ltd. Co. Hungary

Information update date: & nbsp30.09.2015

Illustrated instructions

Instructions

Fluconazole-Teva (Fluconazole-Teva)