2010/09/21

Ancotyl

Composition, structure and packing

Solution for infusion transparent, colorless or nearly colorless, admitted the presence of a crystalline precipitate which dissolves on heating the vial to 80 ° C not more than 30 minutes.

1 ml 1 vial. flutsitozin (5-FC) 10 mg 2.5 PM

Excipients: sodium chloride, trometamol, hydrochloric acid 25% (up to pH 7.4), water d / and.

Clinico-pharmacological group: Antifungal drug.

Pharmacological action

Antifungal drug fluorinated pyrimidine. In cells susceptible flutsitozin through specific tsitozindezaminazy deaminated to 5-fluorouracil, which is embedded in the RNA agent instead of uracil, thereby violating the synthesis of protein. In addition, suppressed the activity timidilatsintetazy that leads to disruption of DNA synthesis of the fungus. In vivo and in vitro drug has a fungistatic and fungicidal effect against yeast fungi, agents of cryptococcosis and hromoblastomikoza. In aspergillosis Ankotil shows fungistatic activity.

Minimum inhibitory concentration - 0.03-12.5 mg / l. When treating Ankotilom have initially sensitive to it gradually strains may develop resistance, therefore, to determine the sensitivity should be carried out before and during treatment (based on tests and appropriate growth media, free of antagonists, it is recommended disc tests with 5-FC).

Pharmacokinetics

Distribution

The drug is well distributed in tissues and body fluids, also diffuses into the cerebrospinal fluid. Vd after i / v administration of 0.8 L / kg. Binding to plasma proteins is low and amounts to 2-4%. The concentration of the drug in the cerebrospinal and peritoneal fluid is approximately 75% of the level of concentration in the serum.

Metabolism

A small number flutsitozina deaminated to 5-fluorouracil.

Removing 90% of the dose appears flutsitozina kidneys unchanged (glomerular filtration). In adults and children with normal renal function, T1 / 2 is 3-6 h. In normal renal function the concentration in urine is always much higher than in serum.

Pharmacokinetics in special clinical situations

As shown Ankotil kidneys virtually unchanged, with renal dysfunction increases T1 / 2. T1 / 2 in premature infants is 6-7 hours

Statement

Ankotil used to treat systemic infections caused by yeast and other fungal pathogens, sensitive to the effects of the drug:
generalized candidiasis;
cryptococcosis;
hromoblastomikoz;
aspergillosis (only in combination with amphotericin B);
infections caused by fungi Torulopsis glabrata and Hansenula.

Dosage regimen

The drug is introduced into / to drip; allowed direct i / in the introduction of a central venous catheter or through the introduction of peritoneal infusion. The recommended daily intake for adults and children is 200 mg / kg of body weight, divided into 4 doses, entered within 24 hours

For the treatment of candidiasis of the urinary tract daily dose is 100 mg / kg. For patients with diseases caused by highly sensitive to the drug agents, may be sufficient to introduce a daily dose of 100-150 mg / kg. In this case a smaller dose also has an adequate effect. The standard single dose of 37.5-50 mg / kg of body weight and put through a short infusion (20-40 min), provided that the water balance in the patient.

In normal renal function intervals between treatments - 6 pm Duration of treatment was 1 week. In acute infections (sepsis kandidamikotichesky) duration of treatment is 2-4 weeks. In subacute and chronic cases is usually required, a longer treatment, and recommended the combined use of amphotericin B. Ankotila and

In the treatment of cryptococcal meningitis, treatment duration is not less than four months.

In case of violation of renal function should be prescribed lower doses and increase the intervals between treatments.

Creatinine clearance

The intervals between the administration of single doses of 50 mg / kg body weight (a single dose)> 40 ml / min for 6 h 40-20 ml / min for 12 h 20-10 ml / min 24 hours

When CC less than 10 ml / min should determine serum concentrations flutsitozina 12 hours after the first dose.

With the introduction of subsequent doses of the drug concentration in serum flutsitozina must be maintained in the range of 25-50 micrograms / ml and should not exceed 80 ug / ml. Flutsitozin effectively removed from the body means hemodialysis, peritoneal dialysis and hemofiltration.

In carrying out these procedures is achieved clearance, approximately equal to creatinine clearance. Duration of therapy is determined individually. The dose for infants is calculated the same way as for adults and children.

This should take into account the high probability of imperfections in renal function, characteristic of this age, or are the result of the toxic to the kidneys therapy. It is recommended that regular monitoring of the concentration flutsitozina in serum and, if necessary, the corresponding correction dosing regimen.

In the presence of renal dysfunction should increase the intervals between the administration of single doses of the drug, as indicated in the table above. If renal dysfunction were found, but noted the excess of the recommended level of concentration flutsitozina in serum, it is recommended to reduce the dose, leaving at the same level of treatment intervals between treatments.

Dosage regimen and profile of side effects in elderly patients are similar to those established for other age groups. Particular attention in this age group should be given to monitoring renal function.

Application Ankotila in combination with amphotericin B on the basis of experimental data used Ankotila in combination with amphotericin B, in many cases provides a synergistic or at least an additive effect. Clinical studies have shown that the combination of these two drugs gives a better therapeutic effect than each monotherapy. In addition, combination therapy can reduce the therapeutic dose of amphotericin B and, thus, its toxic side effects. At the same time reduces the duration of treatment. Finally, the use of combination therapy can prevent or delay the development of secondary resistance of pathogens observed in monotherapy Ankotilom. The use of combination therapy is especially effective in the treatment of cryptococcosis, as well as subacute and chronic fungal infections (meningoencephalitis, endocarditis, candidiasis uveitis).

In the conduct of combined therapy for treatment of Cryptococcosis CNS recommend the following dosing regimen. Ankotil prescribe a dose of 150 mg / kg / day in the form of rapid infusion.

In renal insufficiency the dose should be reduced according to creatinine clearance. Amphotericin B administered in a dose of 0.3 mg / kg / day (from the increase in dose). The drug injected infusion for 3-4 h, as follows: - 1 Day: test-dose of 1 mg (control of temperature, pulse, respiratory rate and blood pressure within 3 h).
in the absence of adverse reactions in the 1 st day of starting treatment: injected 0.3 mg / kg of the drug + hydrocortisone 25 mg / day.
in the presence of adverse drug dose increased gradually. Day 1: 0.1 mg / kg + 50 mg of hydrocortisone, 2-day: 0.2 mg / kg + 50 mg of hydrocortisone, the third day: 0.3 mg / kg + 50 mg of hydrocortisone. It should be as early as possible to reduce the dose of hydrocortisone or completely abolish its introduction. - A heavy, difficult to treat cases, especially with aspergillosis, a dose of amphotericin B may be increased to 0.5-0.6 mg / kg / day.

Depending on the form of the disease and individual tolerance duration of therapy can last up to 6 weeks, in some cases and more. Note that the infusion solution Ankotila incompatible with amphotericin B. We must not confuse a single drip infusion solution Ankotila and amphotericin B. According to the aforementioned dose regimen for patients with normal renal function, appoint a full dose Ankotila and only about half the usual dose of amphotericin B. However, even this reduced dose of amphotericin B may reduce the clearance of creatinine, respectively, to reduce the excretion of flutsitozina from the body. In such cases, the dose Ankotila decrease according to the degree of renal failure.

Side effect

Since the cardiovascular system: heart failure, ventricular dysfunction, pain behind the sternum.

The respiratory system: respiratory arrest, dyspnoea.

On the part of the digestive system: nausea, vomiting, abdominal pain, diarrhea, anorexia, dry mouth, duodenal ulcer, gastrointestinal bleeding, ulcerative colitis, abnormal liver function, jaundice, increased liver enzymes, hyperbilirubinemia, and in rare cases debilitated patients was observed acute hepatic failure, sometimes fatal.

From the central nervous system and peripheral nervous system: ataxia, hearing loss, headaches, paresthesia, parkinsonism, peripheral neuropathy, dizziness, sedation, seizures, loss of a clear perception of reality, hallucinations, psychosis.

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

The part of the hemopoietic system: anemia, agranulocytosis, aplastic anemia, eosinophilia, leykotsitopeniya, pancytopenia, thrombocytopenia, hemolytic anemia. In individual cases, debilitated patients (on the background of existing immunosuppression) showed signs of depression hematopoiesis in bone marrow (pancytopenia). In this category of patients, these symptoms may be irreversible.

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

Other: fatigue, weakness, hypersensitivity, pyrexia, hypoglycemia, hypokalemia.

Contraindications
Hypersensitivity to flutsitozinu or other components of the drug (including history).

Pregnancy and lactation

Controlled studies on the use of the drug during pregnancy in women was carried out. Therefore Ankotil should be appointed only in those cases when the expected therapeutic effect for the mother outweighs the potential risk for the development of the fetus. Unknown is allocated whether the active substance in the breast milk. Given the importance of treatment with this drug to the mother, the physician must decide whether to breast-feed.

Application for violations of liver function

It should monitor indicators of liver function on a daily basis at the beginning of treatment, then - 2 times a week.

Application for violations of renal function

In case of violation of renal function should be prescribed lower doses and increase the intervals between treatments. When CC less than 10 ml / min should determine serum concentrations flutsitozina 12 hours after the first dose.

With the introduction of subsequent doses of the drug concentration in serum flutsitozina must be maintained in the range of 25-50 micrograms / ml and should not exceed 80 ug / ml. Flutsitozin effectively removed from the body means hemodialysis, peritoneal dialysis and hemofiltration. In carrying out these procedures is achieved clearance, approximately equal to creatinine clearance.

Duration of therapy is determined individually. Note that it is necessary to monitor renal function in patients with (preferably by determining creatinine clearance) before and during treatment. If necessary the corresponding correction dosing regimen.

Cautions

Ankotil should not be used in patients with renal insufficiency in the absence of equipment, allowing to monitor the level of concentration flutsitozina in serum. Caution must be exercised in applying the drug in patients with suppressed bone marrow hematopoiesis, or blood diseases. Must be taken picture of the peripheral blood and indicators of liver function on a daily basis at the beginning of treatment, then - 2 times a week.

When measuring the concentration of flutsitozina in serum should be aware that flutsitozina concentration in blood samples taken during or immediately after drug administration, nonexponential for subsequent recovery flutsitozina concentration in serum. In order to monitor the level of serum flutsitozina recommended a blood test shortly before the next procedure.

Note that it is necessary to monitor renal function in patients with (preferably by determining creatinine clearance) before and during treatment.

If necessary the corresponding correction dosing regimen. Before and during treatment with Ankotil recommended to determine the sensitivity of pathogens to flutsitozinu. For this purpose, tests, and appropriate nutrient medium, free of antagonists. We recommend the use of disk tests with flutsitozinom. In patients with renal insufficiency should monitor renal function at least 1 time per week.

In determining the level of creatinine using the two-step enzymatic analysis may distort the results of analysis (false-positive azotemia) because of the influence flutsitozina. You must use other methods of determining creatinine.

In the calculations of the introduction of electrolyte solutions for patients with renal and / or heart failure, as well as violation of electrolyte balance must take into account the amount of input infusion solution Ankotila and sodium content (138 mg / dL).

Overdose

Cases of overdose are unknown. In case of overdose may increase the risk of known adverse reactions and the severity of their manifestation. When serum flutsitozina more than 100 mg / l, supported for a long time, it was noted worsening of side effects.

Лечение: в случае передозировки следует обеспечить поступление в организм достаточного объема жидкости (при необходимости назначают в/в введение), поскольку флуцитозин выводится через почки в неизменном виде.

Required frequent monitoring of peripheral blood parameters, as well as careful monitoring of renal function and liver. In the case of deviations from the norm should apply the appropriate therapeutic measures. Since hemodialysis reduces serum concentrations flutsitozina in patients with anuria, we can consider the use of dialysis as a method of therapy in case of overdose Ankotila.

Drug Interactions

In studies in vitro and in vivo studies have shown that the combined use of amphotericin B Ankotila and their activities are mutually reinforced against many strains of pathogens. This effect was especially pronounced in the case of pathogens, low sensitivity to Ankotilu.

When applied simultaneously with cytostatic Ankotila increased risk of leukopenia (particularly neutropenia, often accompanied by thrombocytopenia). Therefore, the need to designate this combination should monitor the composition of peripheral blood. Due to the fact that the removal flutsitozina performed almost exclusively by the kidneys, all drugs that reduce glomerular filtration, increasing its half-life. In such cases, regular monitoring creatinine clearance, as well as appropriate dosage adjustment.

Pharmaceutical interactions

Note that the infusion solution Ankotila incompatible with amphotericin B. These drugs must be administered separately. Ankotil can be used in conjunction with parenteral solutions of sodium chloride 0.9% or 0.18% and dextrose 5% and 4%. Not allowed to add other drugs to the infusion solution Ankotila.

Terms and Conditions of storage

The drug should be stored out of reach of children, at a temperature of 18 ° to 25 ° C. Do not apply in the case of precipitation! Storage at temperatures below 18 ° C can lead to the formation of sediment.

The precipitate is dissolved by heating the vial to 80 ° C not more than 30 minutes. Storage at temperatures above 25 ° C can help to make flutsitozina in cytostatic fluorouracil, with the appearance of the solution does not change.

Shelf life - 2 years.