Flucytosine

When ATH:
J02AX01

Characteristic.

Ftorirovannyj pyrimidine. White or almost white, crystalline powder;. Solubility in water 1,5 g / 100 ml at 25 °C. pKa₁ 3,26. Molecular weight 129,09.

Pharmacological action.
Antifungal, fungistatic, fungicidnoe.

Application.

Systemic infections, caused by yeast and other fungal pathogens, sensitive to flucytosine: generalized candidiasis; kryptokokkoz; chromoblastomycosis; aspergillosis (only in combination with amfoteritinom b); infection, caused by microorganisms Torulopsis glabrata and Hansenula.

Contraindications.

Hypersensitivity, chronic renal failure if you can not determine the concentration in the blood serum flucytosine.

Restrictions apply.

Inhibition of bone marrow function, blood disease.

Pregnancy and breast-feeding.

Teratogenic effects. Flucytosine showed birth defects (fusion of the vertebrae) in rats when administered at doses 40 mg / kg / day (298 mg / m²/d; 0,051 MRDC) from the 7th to the 13th day of pregnancy. Flucytosine when administered in higher doses (700 mg / kg / day; 5208 mg / m²/d; 0,89 MRDC) from the 9th to the 12th day of pregnancy were recorded such malformations, as congenital cleft lip, cleft palate, and the small size of the upper jaw. Flucytosine showed no teratogenicity in rabbits at doses up to 100 mg / kg / day (1423 mg / m²/d; 0,243 MRDC) when administered in the 6th to 18th day of pregnancy. In mice dose of flucytosine 400 mg / kg / day (1380 mg / m²/d; 0,236 MRDC), entered from the 7th to 13th day of pregnancy, associated with low frequency (statistically not significant) occurrence of cleft palate.

There are no adequate and well-controlled studies in pregnant women has not been. If pregnancy can be given only in cases, when the expected therapeutic benefit outweighs the potential risk to the fetus (It passes through the placenta).

Category actions result in FDA - C. (The study of reproduction in animals has revealed adverse effects on the fetus, and adequate and well-controlled studies in pregnant women have not held, However, the potential benefits, associated with drugs in pregnant, may justify its use, in spite of the possible risk.)

Not installed, whether flucytosine penetrates the mother's milk. During breastfeeding you need to decide on the termination of breastfeeding, or termination of therapy flucytosine, Considering the importance of her mother.

Side effects.

Cardio-vascular system and blood (hematopoiesis, hemostasis): cardiac arrest, violation of ventricular function, anemia, agranulocytosis, aplasticheskaya anemia, eozinofilija, leukopenia, thrombocytopenia, gemoliticheskaya anemia; in rare cases, debilitated patients (against the background of existing immunosuppression) — signs of oppression of hematopoiesis in the bone marrow (pancytopenia), in these patients, these symptoms may be irreversible.

From the respiratory system: respiratory arrest, chest pain, breathlessness.

For the skin: rash, itch, hives, photosensitivity, toxic epidermal necrolysis.

From the digestive tract: nausea, vomiting, abdominal pain, diarrhea, anorexia, dry mouth, duodenal ulcer, gastrointestinal bleeding, yazvennыy colitis, increased levels of bilirubin, abnormal liver function, jaundice, elevated liver enzymes in serum; in a few cases the weakened patients acute liver failure, sometimes fatal.

With the genitourinary system: azotemia, increased levels of creatinine / urea / nitrogen, kristallurija, acute renal failure.

From the nervous system and sensory organs: ataxia, unusual tiredness, weakness, headache, paraesthesia, parkinsonizm, peripheral neuropathy, dizziness, sedation, convulsions, loss of consciousness, hallucinations, psychosis, hearing loss.

Other: allergic reactions, fever, gipoglikemiâ, kaliopenia.

Cooperation.

Studies in vitro and live It was shown, that the combined use of amphotericin B and flucytosine their activity is synergistic against many strains of (This effect is particularly pronounced in the case of pathogens, little sensitive to flucytosine).

Since the treatment of flucytosine there is a risk of leucopenia (particularly neutropenia, often accompanied by thrombocytopenia), while the treatment with cytostatics requires the daily monitoring of peripheral blood. Since the excretion of flucytosine almost exclusively via the kidneys, then PM, reduce glomerular filtration, increase T_1/2 Flucytosine (It requires regular monitoring of creatinine clearance, as well as appropriate dose adjustment).

Infusion solutions flucitozina and amphotericin b should be separately. Flucytosine can be used simultaneously with parenteral solutions 0,9 or 0,18% sodium chloride and 5 and 4% Glucose. No other drugs should not be added to infusion solutions flucytosine.

Overdose.

Cases overdose unknown.

Symptoms (possible): increased risk of adverse reactions and the severity of their symptoms. Excess serum concentration for a long time over 100 mg/l has been accompanied by a growing number of side effects, especially from the gastrointestinal tract (diarrhea, nausea, vomiting), hematological (leukopenia, thrombocytopenia), of the liver (hepatitis).

Treatment: should ensure intake of adequate fluid volume (if necessary, in / in a), as flucytosine eliminated via the kidneys in unchanged form. Requires frequent monitoring of peripheral blood parameters, as well as careful monitoring of renal and hepatic function. In the case of deviations from the norm to apply appropriate therapeutic measures. Since hemodialysis significantly reduces serum concentrations of flucytosine in patients, suffering anuriei, It can be considered for use in dialysis as a method of therapy in cases of overdose flucytosine.

Dosing and Administration.

B / using a dropper; permitted the direct I / O through the introduction of a central venous catheter or infusion administration by peritoneal.

The recommended dose for adults and children is 100-200 mg/kg/day (depending on the indication and sensitivity of micro-organisms), razdelennaya of 4 dose, for input 24 no. Single dose is 37.5-50 mg/kg is entered through short infusions (20-40 Minutes) provided that an adequate hydration of the patient. Normal kidney function, the intervals between procedures- 6 no. The duration of therapy is determined individually. Usually, duration of treatment is 1 Sun, in acute infections (for example kandydamykotycheskyy sepsis) -2-4 weeks; subacute and chronic infections required, usually, longer treatment, It recommended the combined use with amphotericin B; in the treatment of cryptococcal meningitis is not less than 4 Months.

If the kidney function should be prescribed lower doses and to increase the interval between procedures depending on creatinine clearance; creatinine clearance <10 mL / min determined by serum concentration of flucytosine 12 hours after the first dose. With subsequent doses of the drug concentration in serum should be maintained in the range 25-50 ug / ml and should not exceed 80 ug / ml.

The dose for infants is calculated as, both for adults and children. It should take into account the greater likelihood of renal dysfunction, inherent in this age, or is a consequence of the toxic renal therapy. It is recommended to monitor the levels in the serum and flucytosine, in case of need, corresponding adjustment of dosing regimen. If the kidney function should increase the interval between administration of single doses of the drug. If renal dysfunction is detected, but it is experiencing higher than the recommended level of concentration in the serum flucytosine, it is recommended to reduce the dose, leaving at the same level mode intervals between treatments.

The dosage regimen and the profile of side effects in the elderly are similar to those, are set for the other age groups (particular attention in this age group should be given to monitoring of renal function).

Precautions.

With extreme caution should be used in patients with impaired renal function. All patients should be evaluated before the start of therapy, and then during treatment carefully monitor kidney function (preferably by determining the creatinine clearance), liver and peripheral blood picture. In patients with renal insufficiency should be monitored kidney function at least 1 times a week. It should not be given to patients, suffering from renal failure, in the absence of the apparatus, allows you to monitor the concentration of serum flucytosine. Caution should be exercised when used in patients with bone marrow suppression or blood diseases. There is a need to control picture peripheral blood and liver function every day at the beginning of treatment, then - 2 times a week.

Avoid prolonged maintenance of concentrations of more than 100 mg/l due to increased risk of adverse reactions.

When measuring the level of serum flucytosine be considered, concentration in blood samples, taken during or directly after injection, unrepresentative for the subsequent rise in serum concentrations of flucytosine. In order to monitor the serum concentration recommended a blood test shortly before the following procedure.

In determining the level of creatinine using a two-step enzyme assay does not exclude distortion of the analysis results (false positive azotemia) due to the influence of flucytosine. It is necessary to use other methods for the determination of creatinine.

When calculating the volume of administration of electrolyte solutions for patients, suffering from renal and / or heart failure, as well as electrolyte imbalance, must take into account the amount of input infusion solution flucytosine and sodium content (138 mmol / l).

Cooperation