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

Dosage of 50 mg: hard gelatin capsules with the trademark "Pharmaceutical Company Health" LLC, registered on them, No. 3, with opaque white lid and body.

Dosage of 100 mg: hard gelatin capsules with the trademark "Pharmaceutical company" Zdorovie "LLC, printed on them, № 2, with opaque yellow lid and body.

Dosirok 150 mg: hard gelatin capsules with the trademark "Health Company" Health Company No. 1, printed on them, with opaque green lid and body.

Contents of capsules: a homogeneous white powder with a creamy shade of color.

Pharmacotherapeutic group:Antifungal agent.

ATX: & nbsp

J.02.A.C Triazole derivatives

J.02.A.C.01 Fluconazole

Pharmacodynamics:

Antifungal agent, has a highly specific effect, inhibiting the activity of enzymes of fungi, dependent on cytochrome P450. 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.

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

Pharmacokinetics:

Absorption of fluconazole is high (food does not affect the rate of absorption), bioavailability is 90%. TCmax after oral administration of 150 mg - 0.5-1.5 hours. Cmax, when administered orally, is 90% of the plasma concentration when given intravenously at a dose of 2.5-3.5 mg / kg. The connection with plasma proteins is 11-12%.

The concentration in the plasma is in direct proportion to the dose. The equilibrium concentration (Css) is reached by the 4-5 day of intake (when 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 vaginal secretions are reached 8 hours after ingestion and are kept at this value for at least 24 hours. It penetrates well into the cerebrospinal fluid, in fungal meningitis the concentration in the cerebrospinal fluid is about 85% of that in the plasma. In the fluid, epidermis and stratum corneum (selective accumulation), concentrations exceeding serum levels are achieved. After oral administration of 150 mg on Day 7, the concentration in the stratum corneum is 23.4 μg / g, and 1 week after the second dose, 7.1 μg / g; concentration in the nails after 4 months of application in a dose of 150 mg once a week - 4.05 μg / g in healthy and 1.8 μg / g in the affected nails. The volume of distribution approximates the total water content in the body.

T1 / 2 - 30 hours. It is an inhibitor of the isoenzyme CYP2C9 in the liver. It is excreted mainly by the kidneys (80% - unchanged, 11% - in the form of 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 creatinine clearance. After hemodialysis for 3 hours the concentration of fluconazole in plasma is reduced by 50%.

Indications:

Systemic lesions caused by fungi of Cryptococcus, including meningitis, sepsis, an infection of the lungs and the skin, in patients with a normal immune response, and in patients with various forms of immunosuppression (including AIDS patients, organ transplantation); prevention of cryptococcal infection in AIDS patients. Generalized candidiasis: candidemia, disseminated candidiasis (with the defeat of the endocardium, abdominal organs, respiratory organs, eyes and urinary organs), including in patients receiving a course of cytotoxic or immunosuppressive therapy, as well as the presence of other factors predisposing to their development. - treatment and prevention.

Candidiasis of mucous membranes: oral cavity, pharynx, esophagus, non-invasive

bronchopulmonary candidiasis, candiduria, mucocutaneous and chronic atrophic oral candidiasis (associated with wearing dentures).

Genital candidiasis: vaginal (acute and recurrent), 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: stop, body, inguinal area, onychomycosis, pityriasis, skin candidiasis infections.

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

Contraindications:

Hypersensitivity to fluconazole (including other azole antifungal drugs in history), simultaneous reception of terfenadine (against the background of a constant intake of fluconazole at a dose of 400 mg / day or more) and astemizole, lactation period, children under 3 years old. Deficiency of lactase, lactose intolerance, glucose-galactose mal absorption.

Carefully:

Use with caution in liver failure; the appearance of a rash against the background of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections; with concurrent administration of terfenadine and fluconazole at a dose of less than 400 mg / day, with potentially pro-rhythmogenic conditions in patients with multiple risk factors (organic heart disease, electrolyte balance disorders, concomitant administration of medications that cause arrhythmias).

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 defects 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 use of fluconazole has not been established.

Fluconazole should be avoided during pregnancy, except in cases of severe and potentially life threatening mothers of fungal infections, when the expected benefit of treating the mother exceeds the possible risk to the fetus. Women of childbearing age should use reliable contraceptive during treatment and within 7 days after the end of treatment, and before the appointment of the drug, make sure that there is no pregnancy.

Fluconazole penetrates into breast milk in concentrations close to plasma. If

use of the drug is necessary, you should stop breastfeeding before starting treatment.

Dosing and Administration:

Assign 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:

In cryptococcal infections, candidemia, disseminated candidiasis and other invasive candidiasis infections, 400 mg is prescribed on the first day, then 200-400 mg once a day. The duration of treatment depends on the clinical and mycological response (for cryptococcal meningitis is at least 6-8 weeks).

For the prevention of cryptococcal meningitis in AIDS patients after completion of a full course of primary treatment with fluconazole at a dose of 200 mg / day can continue for a long time.

When oropharyngeal candidiasis is prescribed 50-100 mg once a day for 7-10 days, in patients with immunosuppression - 14 days or more. To prevent the recurrence of oropharyngeal candidiasis in AIDS patients after completing the full course of primary therapy, 150 mg once a week are prescribed.

At atrophic oral candidosis, associated with the wearing of dentures, 50 mg once a day for 14 days are prescribed in combination with local antiseptic medicines to treat the prosthesis.

In other candidiasis of the mucous membranes (with the exception of genital candidiasis), 50-100 mg once a day is prescribed for 14-30 days.

With vaginal candidiasis appoint 150 mg once. To reduce the frequency of relapses apply once a month for 150 mg for 4-12 months, sometimes you may need more frequent use.

With balanitis caused by Candida, appoint 150 mg / day once.

For the prevention of candidiasis, the recommended dose is 50-400 mg / day, depending on the degree of risk of 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 / 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 treatment is continued for another 7 days.

In case of skin lesions, including mycosis of the feet and skin of the inguinal region, candidiasis is prescribed 150 mg once / week or 50 mg 1 time / day. The duration of therapy is usually

2-4 weeks, however, with foot mycoses, longer therapy (up to 6 weeks) may be required.

With pityriasis, lishae are prescribed 300 mg once a week for 2 weeks.Some patients require a third dose of 300 mg once a week, while for a portion of patients a single dose of 300-400 mg is sufficient. An alternative treatment regimen is the use of 50 mg 1 time / day for 2-4 weeks.

With onychomycosis appoint 150 mg once a week. Treatment should continue until the replacement of the infected nail (the growth of uninfected nails). For the repeated growth of nails on the fingers and toes, the norm normally requires 3-6 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.

At deep endemic mycoses appoint 200-400 mg / day for up to 2 years. Duration of therapy is determined individually and can be 11-24 months with coccidioidomycosis, 2-17 months with paracoccidioidomycosis, 1-16 months with sporotrichosis and 3-17 months with histoplasmosis.

Children over 3 years:

In children, as with similar infections in adults, the duration of treatment depends on the clinical and mycological effects.In children, the drug should not be used in a daily dose that would exceed that of adults. The drug is used daily 1 time per day, using suitable dosage forms of fluconazole.

Candidiasis of the esophagus is prescribed 3 mg / kg / day for at least 3 weeks and within 2 weeks after the regression of symptoms. When candidiasis of the mucous membranes - 3 mg / kg / day for at least 3 weeks, in the treatment of generalized candidiasis and cryptococcal infection (including meningitis) - 6-12 mg / kg / day for 10-12 weeks (before laboratory confirmation absence of pathogens in CSF).

For the prevention of fungal infections in children with reduced immunity, who have a risk of developing infection associated with neutropenia, resulting from cytotoxic chemotherapy or radiation therapy, 3-12 mg / kg / day are prescribed, depending on the severity and duration of preservation of induced neutropenia. For 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.

The maximum daily dose for children is 400 mg.

Elderly patients

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

Patients with impaired renal function

Adult patients with impaired renal function are initially given a "shock" dose of 50-400 mg, after which the daily dose is determined depending on the creatinine clearance according to the following table.

Creatinine clearance (ml / min)	Percent of Recommended Dose
>50	100%
11-50 (without dialysis)	50% every 24 hours or 100% every 48 hours
Patients on dialysis	100% after each dialysis session

Side effects:

The incidence of side effects is classified according to WHO recommendations: very often -> 10%, often -> 1%, but <10%; infrequently -> 0,1%, but <1%; rarely -> 0.01%, but <0.1%; very rarely - <0.01%. The most common side effects observed during clinical trials of fluconazole are headache, skin rash, abdominal pain, diarrhea, and nausea.

From the nervous system: often - headache; infrequently - dizziness, parasthesia, convulsions, seizures, tremor, insomnia, drowsiness, general weakness, increased fatigue.

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

From the digestive system: often - decreased appetite, nausea, vomiting, diarrhea, abdominal pain; infrequently - anorexia, constipation,dyspepsia, flatulence, dryness of oral mucous membranes, taste change, toothache.

From the side of the liver and bile-excreting tracts: often clinically significant

increased 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%), icteric sclera; rarely - a violation of liver function, hepatocellular necrosis, including fatal

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

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

From the organs of hearing and balance: infrequently - vertigo.

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

From the musculoskeletal system: infrequently - myalgia.

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

Other: rarely - a violation of kidney function, alopecia.

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

Overdose:

Symptoms: hallucinations, paranoid behavior.

Treatment-, symptomatic: gastric lavage, formed diuresis. Hemodialysis within 3 hours reduces the plasma concentration by approximately 50%.

Interaction:

Fluconazole increases efficiency coumarin anticoagulants (prolonged prothrombin time to warfarin - on average 12%) in the blood concentration of zidovudine with increasing frequency of its side effects, cyclosporine (when using Fluconazole, 200 mg / day), rifabutin (while applying described uveitis cases) and phenytoin to a clinically significant degree (the combined use requires monitoring of phenytoin concentration in plasma).

With simultaneous application fluconazole increases plasma concentrations and the risk of developing cardiotoxic effects of astemizole; prolongs half-lifetheophylline with an increased risk of intoxication (the dose correction of theophylline is necessary); increases the concentrations of midazolam and triazolam with a potential risk of developing psychomotor effects (more pronounced when fluconazole is administered orally than with intravenous administration); increases the concentration of tacrolimus with an increased risk of nephrotoxicity.

Fluconazole can induce an increase in the Q-T interval, so when using it with drugs prolonging the Q-T interval, careful monitoring of patients is necessary, since additive effects can not be ruled out.

With the simultaneous administration of fluconazole and zipraside, cardiac rhythm disturbances occur, including arrhythmias of the "pirouette" type.

With the simultaneous use of fluconazole with terfenadine, the concentration of terfenadine in the blood plasma increases, which leads to an increase in the frequency of heartbeat, tachycardia, dizziness, chest pain, Q-T interval prolongation, increased risk of arrhythmias, including paroxysms of ventricular tachycardia (torsades de points).

With the simultaneous administration of fluconazole with derivatives of sulfonylureas

(chlorpropamide, glibenclamide, glipizide and tolbutamide) should periodically monitor the concentration of glucose in the blood and, if necessary, adjust the dose of hypoglycemic drugs (fluconazole extends their half-life).

Hydrochlorothiazide increases the concentration of fluconazole in plasma by 40%, rifampicin reduces its half-life by 20% and the area under the pharmacokinetic curve by 25%.

Fluconazole is a potential inhibitor of CYP 2C9 isoenzyme cytochrome P450 and a moderate inhibitor of CYP3A4. With simultaneous application with fluconazole, there is a risk of increasing plasma concentrations of drugs that are metabolized by CYP2C9 or CYP3A4.

With simultaneous application with fluconazole, an increase in serum concentrations of calcium channel antagonists-dihydropyridines (including nifedipine, nicardipine, amlodipine and felodipine), which are metabolized with the participation of CYP ZA4.

The simultaneous use of fluconazole 400 mg and alfentanil at a dose of 20 μg / kg intravenously increases the area under the pharmacokinetic curve by a factor of 2 and reduces the clearance by 55%. In connection with the inhibitory effect of fluconazole on CYP4 simultaneous application with carbamazepine may lead to an increase in the concentration of the latter in blood plasma; with halofantrine - to slow the metabolism of halophantrine, with methadone - to enhance the effects of methadone.

Simultaneous application of fluconazole with inhibitors of HMG-CoA reductase (atorvastatin, simvastatin, fluvastatin) increases the risk of myopathy, with losartan - leads to an increase in the concentration of losartan and a decrease in the concentration of its active metabolite in the blood plasma. If simultaneous administration of fluconazole and HMG-CoA reductase inhibitors is required, the symptoms of myopathy or rhabdomyolysis, the activity of creatine kinase in serum, should be monitored; when it is necessary to simultaneously apply with losartan - the level of blood pressure.

Fluconazole in doses up to 200 mg does not significantly affect the effectiveness of combined oral contraceptives, whereas with the daily intake of 200 mg of fluconazole, the area under the pharmacokinetic curve of ethinylestradiol and levonorgestrel is increased by 40% and 24%, respectively.When receiving 300 mg fluconazole 1 time / week area under the pharmacokinetic curve

Ethinylestradiol and norethindrone increased by 24% and 13%, respectively.

With simultaneous application with fluconazole, it is possible to increase the concentration of amitriptyline and its active metabolite - nortriptyline with increasing toxic effects.

With the simultaneous use of 200 mg fluconazole with celecoxib, a 2-fold increase in the concentration of celecoxib occurs in the blood, therefore the minimum recommended dose of celecoxib should be used.

Patients who have been given long-term therapy with fluconazole combined with prednisone, when fluconazole is withdrawn, careful monitoring of adrenal function is necessary.

Fluconazole inhibits the metabolism of trimetrexate and increases its concentration in the blood plasma, which leads to an increase in the toxic effects of trimetrexate.

Amphotericin B is an antagonist of azole derivatives.

Absorption of fluconazole when taken concomitantly with food, cimetidine, antacids and when applied simultaneously with the general irradiation of the whole organism after bone marrow transplantation, practically do not change.

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, a correction of fungicidal therapy is recommended.

In the course of treatment, it is necessary to monitor blood counts, kidney and liver function. If there are violations of kidney and liver function, stop taking fluconazole.

The hepatotoxic effect of fluconazole is usually reversible, the symptoms disappear after discontinuation of therapy.

Against the background of taking the drug in patients, there were rare cases of development of exfoliative skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Patients with AIDS and malignant neoplasms are more likely to develop severe skin reactions with many drugs. If the patient develops a superficial fungal infection of the rash during treatment, which can be associated with the use of fluconazole, the drug should be discontinued. When rashes appear in patients with invasive / systemic fungal infections

It should be carefully observed and canceled fluconazole with the appearance of bullous lesions or erythema multiforme.

It is necessary to control the prothrombin index while using the coumarinic anticoagulants simultaneously.

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.

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

You should consider the likelihood of developing side effects such as dizziness and convulsions, so caution should be exercised when dealing with potentially dangerous activities requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Capsules of 50 mg, 100 mg and 150 mg.

Packaging:

Capsules of 50 mg and 100 mg No. 10 in a contiguous cell pack together with instructions for medical use in a pack of cardboard.

Capsules of 150 mg No. 1, No. 1x2 No. 1x3, No. 3 in contiguous cell packs, along with instructions for medical use in a pack of cardboard.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.Keep out of the reach of children.

Shelf life:

5 years. Do not use after the period indicated on the package

Terms of leave from pharmacies:On prescription

Registration number:П N015402 / 01

Date of registration:04.12.2008

The owner of the registration certificate:HEALTH PHARMACEUTICAL COMPANY, LTD. HEALTH PHARMACEUTICAL COMPANY, LTD. Ukraine

Manufacturer: & nbsp

HEALTH PHARMACEUTICAL COMPANY, LTD. Ukraine

Information update date: & nbsp15.10.2015

Illustrated instructions

Instructions

Fluconazole (Fluconazole)