Instructions for Fluconazole
Composition Fluconazole:
Active ingredient: Fluconazole -150.00 mg.
Excipients: lactose monohydrate (milk sugar) - 58.49 mg, starch pregelatinization - 18.98 mg, colloidal silicon dioxide - 0.23 mg, magnesium stearate - 2.07 mg, sodium lauryl sulfate - 0.23 mg. Capsule composition 150 mg: capsule body: titanium dioxide –0.8000%, iron dye yellow oxide 0.1%, gelatin - up to 100%; capsule cap: titanium dioxide - 2.0%, iron dye yellow oxide 0.1%, gelatin - up to 100%
Pharmacodynamics Fluconazole:
Fluconazole 150, a representative of a new class of triazole antifungal agents. It has a highly specific effect, inhibiting the activity of enzymes of fungi, dependent on cytochrome P450. Blocks the conversion of lanosterol of fungal cells to ergosterol; increases the permeability of the cell membrane, violates its growth and replication. Fluconazole, being highly selective for cytochrome P450 fungi, almost does not inhibit these enzymes in the human body (in comparison with itraconazole, clotrimazole, econazole and ketoconazole, to a lesser extent, it inhibits cytochrome P450-dependent oxidative processes in human liver microsomes). Does not possess antiadrogenic activity.
Active in opportunistic mycoses, including those caused by Candida spp. (including generalized forms of candidiasis on the background of immunosuppression), Cryptococcus neoformans and Coccidioides immitis (including intracranial infections), Microsporum spp. and Trichophyton spp .; with endemic mycoses caused by Blastomyces dermatidis, Histoplasma capsulatum (including immunosuppression).
Indications Fluconazole:
Systemic lesions caused by Cryptococcus, including meningitis, sepsis, infections of the lungs and skin, both in patients with a normal immune response and in patients with various forms of immunosuppression (including AIDS patients, transplant recipients); supportive therapy to prevent cryptococcal infection in AIDS patients.
Generalized candidiasis: candidemia, disseminated candidiasis (with
damage to the eyes, endocardium, abdominal organs, respiratory organs and urinary organs). Treatment can be carried out in patients with malignant neoplasms and receiving a course of cytostatic or immunosuppressive therapy, as well as in the presence of other factors predisposing to their development - treatment and prevention.
Candidiasis of the mucous membranes: oral cavity, pharynx, esophagus, non-invasive bronchopulmonary candidiasis, candiduria, mucocutaneous and chronic oral atrophic candidiasis (associated with the wearing of dental prostheses).
Genital candidiasis: vaginal (acute and recurrent). Candida balanitis. Preventive use in order to reduce the frequency of recurrences of vaginal candidiasis (three or more episodes per year).
Prevention of fungal infections in patients with malignant tumors on the background of chemotherapy or radiation therapy; prevention of recurrent oropharyngeal candidiasis in AIDS patients.
Skin mycoses: feet, body, groin, onychomycosis, pityriasis versicolor, skin candidal infections.
Deep endemic mycoses (coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis) in patients with normal immunity.
Pharmacokinetics Fluconazole:
Absorption
After oral administration, fluconazole is well absorbed. Simultaneous ingestion of food does not affect the rate of absorption (absorption) of the drug when taken orally. The time to reach the maximum concentration (Tssah) after oral administration on an empty stomach is 150 mg of Fluconazole 150 - 0.5-1.5 hours and amounts to 90% of the plasma concentration when administered intravenously at a dose of 2.5-3.5 mg / l.
Distribution
Plasma concentration is directly dose dependent. Equilibrium plasma concentration of the drug (Css) is achieved by 4-5 days of admission (when taken 1 time per day). The introduction of the "shock" dose (on the first day), which is 2 times higher than the usual daily dose, makes it possible to achieve a concentration corresponding to 90% Css by 2 days. It penetrates well into all body fluids. The concentration of the active substance in breast milk, articular fluid, saliva, sputum and peritoneal fluid is similar to that in plasma. Constant values in the vaginal secretion are reached 8 hours after ingestion and are held at this level for at least 24 hours. It penetrates well into the cerebrospinal fluid (CSF), with fungal meningitis the concentration in CSF is about 85% of that in plasma. In sweat fluid dermis and stratum corneum (selective accumulation), high concentrations exceeding serum levels are achieved. When taken in a dose of 50 mg 1 time per day, the concentration of antifungal agent after 12 days was 73 µg / g, and 7 days after stopping treatment, it was 5.8 µg / L. After ingestion 150 mg 1 time per week. - on day 7, the concentration of Fluconazole 150 in the stratum corneum of the skin was 23.4 µg / g, and 7 days after taking the second dose - 7.1 µg / g.
Concentration in the nails after 4 months of application at a dose of 150 mg 1 time per week: in healthy nails - 4.05 mcg / g, in the affected ones - 1.8 mcg / g. After 6 months after completion of therapy, fluconazole was still detected in the nails.
The apparent volume of distribution (Vd) is close to the total content of extracellular fluid in the body. Communication with plasma proteins is low -11-12%. Metabolism and excretion
The half-life (T1 / 2) is 30 hours. It is an inhibitor of CYP2C9 isoenzyme in the liver. Excreted mainly by the kidneys (80% - unchanged, 11% - in the form of metabolites). Fluconazole 150 clearance is proportional to creatinine clearance. The pharmacokinetics of fluconazole significantly depends on the functional state of the kidneys, while there is an inverse relationship between T1 / 2 and creatinine clearance (CK). After hemodialysis, for 3 hours, the concentration of fluconazole in plasma is reduced by 50%.
The pharmacokinetics of Fluconazole 150 is similar when administered intravenously and by mouth, which makes it easy to switch from one method of administration to another.
Fluconazole Side Effects:
On the part of the digestive system: systems: changes in taste, vomiting, nausea, diarrhea, flatulence, abdominal pain, abnormal liver function (jaundice, hyperbilirubinemia, increased activity of
alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, hepatitis,
hepatocellular necrosis), including fatal.
Of the nervous system: headache, dizziness, convulsions.
Since the cardiovascular system: an increase in the
duration of the QT interval, ventricular fibrillation / flutter.
From the side of blood-forming organs:leukopenia, thrombocytopenia,
neutropenia, agranulocytosis. Allergic reactions', skin rash, erythema multiforme exudative
(including Stevens-Johnson syndrome), toxic
epidermal necrolysis (Lyell's syndrome), anaphylactoid reactions (including angioedema, swelling of the face, urticaria, skin itching).
Other: impaired renal function, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia.
Special conditions Fluconazole:
Treatment should continue until clinical and hematologic remission. Premature discontinuation of treatment leads to relapse.
Treatment can begin in the absence of seeding results or other laboratory tests, but if they are available, an appropriate correction of fungicidal therapy is recommended.
During treatment, it is necessary to monitor blood counts, kidney and liver function. In the event of impaired renal function and liver should stop taking the drug. In rare cases, the use of Fluconazole 150 was accompanied by toxic changes in the liver. In the case of hepatotoxic effects associated with fluconazole, their apparent dependence on the total daily dose, duration of therapy, sex, and age of the patient was not observed. The hepatotoxic effect of Fluconazole 150 is usually reversible; his symptoms disappeared after cessation of therapy. If clinical signs of liver damage appear that may be associated with fluconazole, the drug should be withdrawn.
AIDS patients are more likely to develop severe skin reactions with the use of many drugs. In cases where a rash develops in patients with a surface fungal infection, and it is regarded as definitely associated with fluconazole, the drug should be discontinued. When a rash appears in patients with invasive / systemic fungal infections, they should be carefully monitored and fluconazole should be canceled when a bullous change or erythema multiforme occurs.
Influence on the ability to drive vehicles and mechanisms:
In the event of adverse reactions from the nervous system, patients are advised to refrain from driving and other mechanisms, as well as to be careful when engaging in activities that require increased concentration of attention and quickness of psychomotor reactions.
Contraindications Fluconazole:
simultaneous administration of terfenadine (against the background of continuous administration of antifungal agent at a dose of
400 mg / day or more), astemizole, and other drugs that prolong the QT interval.
simultaneous reception of cisapride
hypersensitivity to the drug or similar in structure azole
compounds
lactose intolerance, lactase deficiency or glucose-galactase malabsorption
children's age up to 3 years (for this dosage form).
Carefully:
Hepatic and / or renal failure, the appearance of a rash associated with the use of Fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections, potentially pro-arrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance, concomitant medication, causing arrhythmias), concomitant use of potentially hepatotoxic drugs, alcoholism. Simultaneous reception of terfenadine and Fluconazole 150 at a dose of less than 400 mg / day.
Pregnancy and lactation:
Use of the drug in pregnant women is impractical, with the exception of severe or life-threatening forms of fungal infections, if the intended benefits of using the drug for the mother outweigh the possible risk to the fetus.
Fluconazole is found in breast milk at the same concentration as in plasma, so its administration during lactation is not recommended.
Drug interaction Fluconazole:
Anticoagulants. antifungal agent increases the prothrombin time of coumarin anticoagulants (for example, warfarin) by an average of 12%, so careful monitoring of the prothrombin time is necessary in patients receiving fluconazole and coumarin anticoagulants.
Sulfonylurea drugs. While taking Fluconazole 150 and oral sulfonylurea drugs (chlorpropamid, glibenclamide, glipizide and tolbutamide), the elimination half-life of the latter is prolonged, which can lead to the development of hypoglycemia. It should periodically monitor the concentration of glucose in the blood and, if necessary, adjust the dose of hypoglycemic drugs.
Hydrochlorothiazide increases the concentration of Fluconazole 150 in plasma by 40%, but this does not require changing the dosage regimen of fluconazole in patients receiving diuretics at the same time.
Phenytoin. Simultaneous reception of fluconazole and phenytoin is accompanied by an increase in the concentration of the latter in a clinically significant degree. Therefore, it is necessary to monitor the level of phenytoin and the selection of its dose to provide therapeutic serum concentrations.
Oral contraceptives. Repeated use of fluconazole (in doses of 50-200 mg) does not affect the effectiveness of the combined contraceptive. Rifampicin. The simultaneous use of Fluconazole 150 and rifampicin led to a reduction in the area under the concentration-time curve by 25% and the half-life of fluconazole by 20%. It is necessary to increase the dose of fluconazole with their simultaneous appointment.
Cyclosporine. In the treatment of Fluconazole 150 at a dose of 200 mg / day. the concentration of cyclosporine in the blood increases. Theophylline. Fluconazole prolongs theophylline's half-life and increases the risk of intoxication (correction of its dose is necessary).
Terfenadine.
Simultaneous reception of Fluconazole in doses of 400 mg / day. and more with terfenadine is contraindicated. antifungal agent treatment in doses of less than 400 mg / day. In combination with terfenadine should be carried out under the close supervision of a physician.
Cisapride. With concurrent use of Fluconazole 150 and cisapride, unwanted heart reactions, including ventricular tachycardia paroxysms (torsades de pointes).
Nifabutin.
Uveitis cases are described.
Tacrolimus. Increases the concentration of tacrolimus, and therefore increases the risk of nephrotoxic action.
Zidovudine. In patients receiving the combination of Fluconazole 150 and zidovudine, an increase in the concentration of zidovudine is observed, which is caused by a decrease in the conversion of the latter to its main metabolite, therefore, an increase in the side effects of zidovudine should be expected.
Midazolam. Increases the concentration of midazolam, in connection with which increases the risk of psychomotor effects (most pronounced when using antifungal agent inside than intravenous).
Dosage Fluconazole:
Inside
Adults with cryptococcal meningitis and cryptococcal infections of other sites usually are prescribed 400 mg on the first day, and then continue the treatment at a dose of 200 mg - 400 mg 1 time / day. The duration of treatment for cryptococcal infections depends on the clinical efficacy confirmed by mycological examination; with cryptococcal meningitis, it is usually continued for at least 6-8 weeks. To prevent the recurrence of cryptococcal meningitis in AIDS patients, after completing the full course of primary treatment, Fluconazole 150 is prescribed at a dose of 200 mg / day for a long period of time.
With candidemia, disseminated candidiasis and other invasive candidal infections, the dose is usually 400 mg on the first day, and then 200 mg each. With insufficient clinical efficacy, the dose of the drug can be increased to 400 mg / day. The duration of therapy depends on the clinical effectiveness.
When oropharyngeal candidiasis, the drug is usually prescribed in 50-100 mg 1 time / day; the duration of treatment is 7-14 days. If necessary, in patients with a pronounced decrease in immunity, treatment may be longer. For the prevention of recurrence of oropharyngeal candidiasis in
AIDS patients after the completion of the full course of primary therapy, the drug may be prescribed 150 mg 1 time per week. In atrophic oral candidiasis associated with the wearing of dentures, fluconazole is usually prescribed 50 mg 1 time per day for 14 days in combination with local antiseptic agents for the treatment of the prosthesis.
other sites of candidiasis (with the exception of genital candidiasis), for example, esophagitis, nsinvasive bronchopulmonary lesions, candiduria, candidiasis of the skin and mucous membranes, etc., the effective dose is usually 50–100 mg / day for a duration of 14–30 days. In vaginal candidiasis, Fluconazole 150 is taken once orally 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 once a month.
The duration of therapy is determined individually; It varies from 4 to 12 months. Some patients may need more frequent use. When balaiitis caused by Candida spp., antifungal agent is administered once at a dose of 150 mg orally. For the prevention of candidiasis, the recommended dose of Fluconazole 150 is 50-400 mg 1 time / day, depending on the degree of risk of developing a fungal infection. If there is a high risk of generalized infection, for example, in patients with expected severe or prolonged neutropenia, the recommended dose is 400 mg 1 time / day. Fluconazole is prescribed a few days before the expected appearance of neutropenia; after increasing the number of neutrophils over 1000 / mm3, treatment is continued for another 7 days.
In case of mycoses of the ruts, including mycoses of the feet, grooves of the inguinal region, and caidiosis of the ruts, the recommended dose is 150 mg 1 time per week or 50 mg 1 time / day. The duration of therapy in normal cases is 2-4 weeks, but with mycoses of the feet, longer therapy may be required (up to 6 weeks). When pityriasis lichen is 300 mg once a week for 2 weeks, some patients require a third dose of 300 mg per week, while in some cases a single dose of 300 mg - 400 mg is sufficient;
An alternative treatment regimen is the use of 50 mg once a day for 4 weeks. For onychomycosis, the recommended dose is 150 mg once a week. Treatment should be continued until the infected nail is replaced (the uninfected nail grows). It takes 6 months and 6-12 months, respectively, for the re-growth of nails on the fingers and feet. However, the growth rate can vary widely among different people, as well as depending on age. For 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 may be 1–24 months with coccidiomycosis; 2-17 months with paracoccidioidomycosis; 1-16 months for sporotrichosis and 3-17 months for 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, that is, no more than 400 mg per day.
The drug is used daily 1 time / day. When candidiasis of the esophagus in children, Fluconazole 150 is administered once a daily dose of 3 mg / kg, in the following medium doses: at the age of 3-6 years (body weight 15-20 kg) - 50 mg; at the age of 7-9 years (body weight 21-29 kg) - 50-100 mg; at the age of 10-12 years (body weight 30-40 kg) - 100-150 mg; at the age of 12-15 years (body weight 40-50 kg) - 100-150 mg. The duration of therapy is at least 3 weeks and for another 2 weeks after the regression of symptoms. In case of candidiasis of the mucous membranes in children, fluconazole is administered once daily in a daily dose of 3 mg / kg, in the following medium doses: at the age of 3-6 years (body weight 15-20 kg) - on the 1st day 100-150 mg, then 50 mg each; at the age of 7-9 years (body weight 21-29 kg) - on the 1st day 100-200 mg, then 100 mg each; at the age of 10-12 lay down (body weight 30-40 kg) - on the 1st day 100-150 mg, then - 50-100 mg each; at the age of 12-15 years (body weight 40-50 kg) - on the 1st day 250-300 mg, then - 100-150 mg each.
The duration of therapy is at least 3 weeks. With generalized candida and cryptococcal infections (including meningitis) in children, Fluconazole is administered once in a daily dose of 6-12 mg / kg, in the following medium doses: at the age of 3-6 years (body weight 15-20 kg) - 100-250 mg; at the age of 7-9 years (body weight 21-29 kg) - 100-300 mg; at the age of 10-12 years (body weight 30-40 kg) - 200-350 mg; at the age of 12-15 years (body weight 40-50 kg) - 250-400 mg. Duration of therapy - within 10-12 weeks (until laboratory confirmation absence of pathogens in the liquor).
For the prevention of fungal infections in children with reduced immunity, in whom the risk of developing an infection is associated with neutropenia developing as a result of cytotoxic chemotherapy or radiation therapy, Fluconazole 150 is prescribed at 3-12 mg / kg / day, depending on the severity and duration of preservation of induced neutropenia, the following average doses: at the age of 3-6 years (body weight 15-20 kg) - 50-250 mg; at the age of 7-9 years (body weight 21-29 kg) - 50-300 mg; at the age of 10-12 lay down (body weight 30-40 kg) - 100-350 mg; at the age of 12-15 years (body weight 40-50 kg) - 100-400 mg.
The duration of therapy is until the elimination of induced neutropenia. In children with impaired night function, the daily dose of the drug should be reduced (in the same proportional relationship as in adults), in accordance with the severity of renal failure. In elderly patients in the absence of renal dysfunction, the usual dosing regimen should be followed. Patients with renal insufficiency (creatinine clearance less than 50 ml / min) dosing regimen should adjust as indicated below. Use of the drug in patients with impaired renal function. Fluconazole is mainly excreted in the urine unchanged.
When taken once, a dose change of ns is required. When you reappoint the drug in patients with impaired renal function, you must first enter the "shock" dose from 50 mg to 400 mg. If creatinine clearance (CC) is 50 ml / min, the usual dose of the drug (100% of the recommended dose) is applied once a day. When QA from 11 to 50 ml / min, a dose of 50% is recommended. Patients who are regularly on dialysis, a single dose of the drug is used after each session of hemodialysis.
Overdose Fluconazole 150:
Symptoms: hallucinations, paranoid behavior.
Treatment: symptomatic, gastric lavage, forced diuresis. Hemodialysis for 3 hours reduces plasma concentration by approximately 50%.
