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

Clinical and pharmacological group: & nbsp

Included in the formulation

АТХ:

J.02.A.X Other antifungal agents for systemic use

J.02.A.X.01 Flucytosine

Pharmacodynamics:

Antifungal agent, fluorinated pyrimidine.

The deamination of flucytosine by the cytosine deaminase of the fungal cell is the conversion to 5-fluorouracil (a powerful antimetabolite). Fluorouracil with the participation of uracilphosphoribosyltransferase is converted to 5-fluoro-UMP, which is phosphorylated to 5-fluoro-UTP (embedded in RNA) or converted to 5-fluorodeoxy-UMP, which, as a potent inhibitor of thymidylate synthase, disrupts the synthesis of fungal cell DNA. As a result, protein synthesis and the cell cycle are disrupted. In mammalian cells, there is no cytosine deaminase capable of deaminating flucytosine, which determines the selectivity of the drug on fungal cells.

In vivo and in vitro, the preparation has fungistatic and fungicidal action against yeast fungi, causative agents of cryptococcosis and chromoblastomycosis. In aspergillosis shows fungistatic activity.

The minimum suppressing concentration is 0,03-12,5 mg / l.

During the treatment, it is possible to develop the resistance of initially sensitive strains, so the sensitivity should be determined before and during treatment.

Pharmacokinetics:

After oral administration, it is well distributed in the tissues and body fluids, diffuses into the cerebrospinal fluid. The volume of distribution after intravenous administration is 0.8 l / kg. Binding to plasma proteins is low and amounts to 2-4%. The concentration in the cerebrospinal and peritoneal fluids is approximately 75% of the concentration in the serum.

A small amount of flucytosine is deaminated into 5-fluorouracil.

90% of the dose of flucytosine is excreted by the kidneys unchanged (glomerular filtration). In adults and children with normal renal function, the half-life period is 3-6 hours. With normal kidney function, the concentration of the substance in the urine is always much higher than in the serum. Because the flucytosine is excreted by the kidneys almost unchanged, with violations of kidney function, the half-life increases.

Half-life in premature infants is 6-7 hours.

Indications:Treatment of systemic mycoses caused by sensitive fungal strains: generalized candidiasis, cryptococcosis, chromoblastomycosis, aspergillosis (only in combination with amphotericin B), infections caused by the fungi Torulopsis glabrata and Hansenula.

ICD-10

I.B35-B49.B37.6 Candidiasis endocarditis (I39.8 *)

I.B35-B49.B37.7 Candida septicemia

I.B35-B49.B37.8 Candidiasis of other localizations

I.B35-B49.B40 Blastomycosis

I.B35-B49.B43 Chromomycosis and pheomycotic abscess

I.B35-B49.B44 Aspergillosis

I.B35-B49.B45 Cryptococcosis

I.B35-B49.B48 Other mycoses, not elsewhere classified

Contraindications:Hypersensitivity to flucytosine. Pregnancy, lactation.

Carefully:Oppression of bone marrow function, blood diseases, AIDS.

Pregnancy and lactation:

Recommendations for FDA - Category C. Qualitative and well-controlled studies on humans have not been conducted, but side effects are not documented. In animal experiments it demonstrates a teratogenic effect. Do not apply!

The application is possible only in cases where the expected benefit of therapy for the mother exceeds the potential risk for fetal development.

There is no information on the penetration into breast milk. Violations are not registered. Do not apply!

Dosing and Administration:

Intravenously with a dropper; direct intravenous administration through the central venous catheter or by peritoneal infusion is permissible.

The usual dosing regimen:

The recommended daily intake for adults and children is 200 mg / kg, divided into 4 doses administered over 24 hours.

For treatment of candidiasis of the urinary tract, a daily dose of 100 mg / kg is usually sufficient.

For patients with diseases caused by highly sensitive flucytosine microorganisms, it may be sufficient to administer a daily dose of 100-150 mg.

The standard single dose is 37.5-50 mg / kg, is administered by means of short infusions (20-40 min) provided that the liquid balance is maintained in the patient's body. With normal renal function, the intervals between procedures are 6 hours.

Typically, the duration of treatment is 1 week.

In acute infections such as candida-septic sepsis, the duration of treatment is 2-4 weeks.

In subacute and chronic cases, longer treatment is required, with a combined use recommended flucytosineand amphotericin B. In the treatment of cryptococcal meningitis, the duration of treatment is at least 4 months.

Side effects:

From the side of cardio-vascular system: heart failure, dysfunction of the ventricles, pain behind the sternum.

From the side respiratory system: respiratory arrest, shortness of breath.

From the side digestive system: nausea, vomiting, abdominal pain, diarrhea, anorexia, dry mouth, duodenal ulcer, gastrointestinal bleeding, ulcerative colitis, impaired liver function, jaundice, increased activity of liver enzymes, hyperbilirubinemia; in isolated cases, weakened patients had acute liver failure, sometimes leading to death.

From the side CNS and peripheral nervous system: ataxia, hearing loss, headaches, paresthesia, parkinsonism, peripheral neuropathy, dizziness, sedation, convulsions, loss of clear perception of reality, hallucinations, psychoses.

From the side urinary system: azotemia, increased levels of creatinine, urea, nitrogen, crystalluria, acute renal failure.

From the side hematopoiesis system: anemia, agranulocytosis, aplastic anemia, eosinophilia, leukocytopenia, pancytopenia, thrombocytopenia, hemolytic anemia. In isolated cases, in weakened patients (against the background of available immunosuppression), signs of oppression of hemopoiesis in the bone marrow(pancytopenia). In this category of patients, these symptoms can be irreversible.

Allergic reactions: rash, itching, hives, photosensitivity, toxic epidermal necrolysis.

Other: fatigue, weakness, excessive sensitivity, pyrexia, hypoglycemia, hypokalemia.

Overdose:

Increased risk of adverse reactions and the severity of their manifestation. Excess of serum concentration over a long time over 100 mg / l is accompanied by an increase in the number of side effects, especially from the gastrointestinal tract (diarrhea, nausea, vomiting), hematologic (leukopenia, thrombocytopenia), liver side (hepatitis).

Treatment: symptomatic therapy, ensuring that sufficient fluids enter the body (if necessary, intravenously), hemodialysis; frequent monitoring of peripheral blood, as well as careful monitoring of kidney and liver function.

Interaction:

Amphotericin B, fluconazole - synergistic effect. Infusion solutions of flucytosine and amphotericin B should be administered separately. Flucytosine can be used simultaneously with parenteral solutions of 0.9 or 0.18% sodium chloride and 5 and 4% glucose.

No other drugs should be added to the infusion solution of flucytosine!

Means that cause blood diseases, myelo-depressants, radiation therapy - an increase in the myelotoxicity of flucytosine.

Means that cause decrease in glomerular filtration rate - increase in the half-life of flucytosine.

Cytarabine - decrease in antifungal activity of flucytosine.

Special instructions:

When measuring the concentration level of 5-fluorouracil in serum, it should be taken into account that the concentration 5-fluorouracil in blood samples taken during or immediately after the administration of the drug, are not indicative of a subsequent increase in the level of concentration 5-fluorouracil in the serum. In order to monitor the level of serum concentration 5-fluorouracil it is recommended that a blood test be performed shortly before the next procedure.

When determining the level of creatinine with the help of two-step enzyme analysis, the results of the analysis (false-positive azotemia) can not be excluded due to the influence of flucytosine. It is necessary to use other methods of determination of creatinine.

Before and during treatment, it is necessary to monitor renal function in patients, preferably by determining the clearance of creatinine.If necessary, the dosage regimen is corrected accordingly.

In patients with kidney failure, kidney function should be monitored at least once a week.

Flucytosine should not be used in patients with renal insufficiency, in the absence of equipment that allows monitoring of the level of concentration 5-fluorouracil in the blood serum.

Care should be taken when using the drug in patients with suppressed bone marrow function or with blood diseases. It is necessary to control the picture of peripheral blood and liver function - daily at the beginning of treatment, then - 2 times a week.

Impact on the ability to drive vehicles and manage mechanisms.

It is necessary to refrain from working with potentially dangerous mechanisms, driving a car and other activities that require increased attention.

Instructions

Flucytosine (Flucytosinum)