Fluconazole

When ATH:
J02AC01

Characteristic.

Antimycotic means of a group of triazole derivatives. Crystalline powder white or nearly white, without smell, with a characteristic taste, difficult to dissolve in water and isopropyl rubbing alcohol, sparingly soluble in ethanol and chloroform, soluble in acetone and easily soluble in methanol (solution isoosmotichen).

Pharmacological action.
Antifungal.

Application.

Kryptokokkoz: cryptococcal meningitis, infections of the skin and the lungs; Prevention of the recurrence of Cryptococcosis in AIDS patients; generalized candidiasis: kandidemija, disseminated candidiasis and other forms of invasive Candida infections (the defeat of the peritoneum, endokarda, eye, respiratory and urinary tract infections); candidiasis mucous membranes of the oral cavity and pharynx, esophagus, bronholegocny candidiasis, kandidurija, kandidozy skin and mucous membranes, atroficski candidiasis of the oral cavity (associated with wearing dentures), Prevention of relapse of oropharyngeal candidiasis in patients with AIDS; Genital candidiasis: vaginal (acute or recurrent), including relapse prevention, kandidoznыj ʙalanit; prophylaxis and treatment of fungal infections in malignant tumors (treatment of zitostatikami and/or radiation therapy), antibiotic therapy, treatment immunodepressantami, after transplantation; mikozy skin (stop, body, groin), chromophytosis, onixomikoz, candidiasis of skin; deep endemic mikozy (coccidiomycosis, parakokcidiomikoz, sporotrichosis, histoplasmosis) in patients with nenarushennym immunity.

Contraindications.

Hypersensitivity, simultaneous terfenadina when reusing doses of fluconazole 400 mg and higher, cisapride (cm. "Interaction").

Restrictions apply.

Known hypersensitivity to other derivative azola, tk. There is no information regarding the cross-hypersensitive between flukonazolom and other azole antifungal means (Caution should be exercised).

Pregnancy and breast-feeding.

When pregnancy is possible only when life-threatening severe infections, if the effect of therapy outweighs the potential risk to the fetus (adequate and well-controlled studies of the safety of use in pregnant women were not conducted). There are reports of various congenital irregularities in infants, whose mother during 3 months or more were treated with high doses of fluconazole is 400-800 mg/day at kokcidioidomikoza, Although the causal relationship of these cases with the acquisition of fluconazole is unclear. At the time of treatment should stop breastfeeding (fluconazole concentration in breast milk compared with plasma).

Side effects.

Patients, receiving a one-time dose in waginalnom 4-8

When conducting comparative clinical studies in the United States in patients with invasive vaginal (n = 448), receiving a one-time dose of fluconazole 150 mg, total frequency of side effects, may be associated with taking medication, made 26%; patients, treated with comparator (n = 448) – 16%. The most common side effects, associated with the acquisition of fluconazole, We were: headache (13%), nausea (7%), abdominal pain (6%), diarrhea (3%), dyspepsia (1%), dizziness (1%), dysgeusia (1%). Most side effects were mild or moderate degree. Very rarely in marketing studies delineate angioneurotic oedema and anaphylactic reactions.

Patients, receiving multiple doses with other infections

In clinical trials, approximately 16% from 4048 patients, treated by fluconazole appear within 7 and more days, observed adverse reactions. Treatment was discontinued because of adverse effects 1,5%, due to abnormalities in lab tests — 1,3% patients.

During treatment flukonazolom clinically expressed side effects have been observed more frequently in HIV-infected patients (21%), In contrast to non-HIV-infected (13%). Number of patients, stopped treatment because of adverse effects, was similar in both groups (1,5%).

Side effects, observed in clinical trials in the treatment flukonazolom during 7 and more days in more than 1% cases and were associated with taking medication (n = 4048): nausea (3,7%), headache (1,9%), skin rash (1,8%), vomiting (1,7%), abdominal pain (1,7%) and diarrhea (1,5%).

Side effects, whose relationship with the treatment flukonazolom likely: gepatotoksichnostь, immunological reactions.

Gepatotoksichnostь.

The combined data for clinical trials and marketing experience show, that treatment flukonazolom accompanied by rare cases of serious toxic reactions on the part of the liver, including death. Revealed no obvious relationship fluconazole-associated hepatotoxicity with a total daily dose, duration of therapy, sex, age of the patients. Gepatotoksicescoe the flukonazola usually (but not always) is reversible, symptoms disappear after cessation of therapy. In order to avoid serious reactions from the liver should carefully monitor patients, which during therapy flukonazom revealed violations of functional liver tests. Treatment flukonazolom should be terminated upon the occurrence of clinically expressed symptoms of developing liver disease, that can be associated with the treatment flukonazolom.

Reaction from the liver can have different severity: from a small transient increase transaminaz liver to clinically expressed hepatitis, Cholestasis, ful′minantnoj liver failure, including death. Cases of fatal hepatic reactions were mainly in patients, suffering from severe underlying medical condition (AIDS, tumor diseases) and often receiving polimedikamentoznuû therapy.

In two trials assessing the efficacy of fluconazole on the prevention of relapse of cryptococcal meningitis was a statistically significant increase in median levels of AST from baseline. Raising transaminaz serum more than 8 times above the upper limit of the norms was noted in about 1% patients, treated flukonazolom. These cases were observed in patients with severe underlying medical condition (AIDS, malignant neoplasms), most of them were receiving multiple concomitant drug therapy, including many HP with a known gepatotoksičnost′û. Frequency increase transaminaz level was higher in patients, receiving simultaneously with start one or more of the following tools: rifampin, phenytoin, Isoniazid, valproic acid, oral gipoglikemicakie means-derived sulfonylureas.

Immunologic reaction: reported rare cases anaphylaxis.

Side effects, whose relationship with the treatment flukonazolom not installed.

CNS: convulsions.

Dermatological: èksfoliativnye skin diseases, including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis; alopecia.

Exfoliativee skin disease when treatment flukonazolom minilaparotomy, in patients with severe major diseases (AIDS, tumor diseases) rarely do they have fatal outcome. If in the face of treatment flukonazolom manifest skin symptoms, requires careful observation of the patient and at increasing symptoms treatment flukonazolom must stop.

Hematopoietic and lymphatic: leukopenia, including neutropenia and agranulocytosis, thrombocytopenia.

Metabolic: hypercholesterolemia, hypertriglyceridemia, kaliopenia.

Side effects, observed in children

In conducting the clinical trial Phase 2 and 3 in the United States and Europe 577 patients aged 1 day − 17 years, treated flukonazolom in doses up to 15 mg/kg/day until 1616 days, side effects in children were observed in 13% cases; patients, treated with comparator (n = 451) - In 9% cases. The most common side effects observed were the following: vomiting (5,4%), abdominal pain (2,8%), nausea (2,3%), diarrhea (2,1%). Treatment was discontinued because of adverse effects 2,3% patients, due to abnormalities in lab tests (in most cases, increased levels transaminaz and alkaline phosphatase) — 1,4% patients.

Cooperation.

Fluconazole enhances the i.e._1/2 from plasma gipoglikemicakih oral drugs-derived sulfonylureas (It is possible to clinically expressed hypoglycemia), increases concentration fenitoina, Zidovudine, Theophylline in the bloodstream. Fluconazole can significantly increase the level of Cyclosporine in the blood of kidney transplant patients with or without renal dysfunction (requires monitoring of Cyclosporine and creatinine in the blood). In a joint application of fluconazole and coumarin-type anticoagulants can lengthen prothrombin time (We recommend careful monitoring of prothrombin time in patients). When coupled with warfarin increases protrombinovoe time on 12%. Rifampicin increases the metabolism of fluconazole: AUC reduced by 25%, T_1/2 from the plasma is on 20% (It should be possible to increase the dose of fluconazole). When taken in conjunction with hydrochlorothiazide for 10 days of fluconazole levels in the plasma of healthy volunteers increased by approximately 40%.

Usage of fluconazole concurrently with HP, those involving the cytochrome P450 enzyme system (incl. terfenadine, cisapride, astemizol) can lead to increased serum levels of these funds (in the absence of accurate information with caution and carefully monitor patients). Given the emergence of serious arrhythmias in patients, received azol′nye other antifungals in conjunction with terfenadine, in concurrent usage of fluconazole and terfenadina careful monitoring of patients. Fluconazole significantly increased the AUC and C_max cisapride; significantly extended QT interval_c patients, at the same time impose cisapride dose 20 mg for 5 days. There have been reports about the development of cardio-vascular disorders, incl. twist of points patients, at the same time taking fluconazole and cisapride.

Cimetidine, Antacids do not affect the induction of fluconazole.

Infusion solution compatible with solutions 20% Glucose, Rïngera, Hartman, potassium chloride in glucose, sodium bicarbonate 4,2%, izotoniceski solution of sodium chloride.

Overdose.

Symptoms: nausea, vomiting, diarrhea, in severe cases, seizures.

Treatment: gastric lavage, diurez, hemodialysis (three-hour dialysis reduces the concentration of drug in plasma is approximately 50%), simptomaticheskaya therapy.

There is one report of an overdose of fluconazole (8200 mg orally) at the 42-year-old HIV-infected patient with development of hallucinations and paranoid behavior. The patient was hospitalized, and his condition returned to normal within 48 no.

Dosing and Administration.

Inside, I /. Dose, route of administration, duration of treatment is determined individually depending on the testimony, the patient's condition, clinical and mikologičeskogo effect. Daily dose depends on the nature and severity of the infection. Children daily dose should not exceed the maximum daily dose for adults. When transferring a patient with on/in the introduction of fluconazole on the reception inside Conversely it is not necessary to change the daily dose.

Adults in chriptokokkoze and generalized 4-in/, inside, 400 mg in 1-St day, then on 200-400 mg/day; When orofaringeal′nom 4-inside, 50-100 mg/day for 7-14 days; in waginalnom 4-8-inside, 150 mg dose, in chronic form 1 Once a month on 150 mg for 4-12 months; mikozah-on 150 mg 1 once a week.

Children with generalized 4-8-6-12 mg/kg/day, 4-8 mucous membranes — 3-6 mg/kg/day, for the prevention of fungal infections is 3-12 mg/kg/day.

Precautions.

In patients with impaired renal function (if Cl creatinine less than 50 ml / min) dosing regimen should be adjusted; When a single admission dose not required.

Newborns in the first 2 weeks of life prescribed in the same dose (mg / kg), as for older children, but the intervals 72 no; at the age of 3-4 weeks — in the same dose at intervals of 48 no.

During treatment, it is necessary to carefully monitor the peripheral blood and the liver. When signs of Hepatotoxicity, rash, bulleznah changes, mnogoformna eritema therapy should be abolished.

Cautions.

Treatment flukonazolom can begin until the results of sowing and other laboratory tests, but after getting the results of these studies, therapy should change accordingly.

Treatment should continue until the advent of clinical/Hematological remission (the exception is sharp vaginal candidiasis). Premature discontinuation of treatment leads to relapse.

Cooperation