Флугарда®

General characteristics. Structure:

Active ingredient: 50 mg of a fludarabin.

Excipients: Mannitolum, sodium hydroxide.

Pharmacological properties:

Pharmacodynamics. Флугарда® - antineoplastic drug, contains a fludarabin phosphate which is the water-soluble fluorinated nucleotide analog of antiviral means of a vidarabin, 9-β-D-арабинофуранозиладенина (ara-A), rather steady against action of an adenosinedeaminase.
 
In a human body of a fludarabin phosphate is quickly dephosphorylated to 2-ftor-ara-A which being taken cells, then intracellularly phosphorylated to active triphosphate (2-ftor-ara-ATF) of dezoksitsitidinkinazy. This metabolite inhibits a DNA polymerase (an alpha, the delta and an upsilon), DNK-praymazu, to DNA-ligase, a ribonukleotidreduktaz and is built in DNA and RNA that leads to DNA replication termination, dysfunction of RNA, processing and broadcast of MRNK. The researches in vitro showed that impact 2-ftor-ara-A on lymphocytes of patients with a chronic lymphoid leukosis (HLL) activates the mechanism of intensive fragmentation of DNA and apoptosis.

It is toxic. Has teratogenic activity. Has no mutagen properties.

Pharmacokinetics. Fludarabina phosphate (2-ftor-ara-AMF) is a water-soluble predecessor of a fludarabin (2-ftor-ara-A). After intravenous administration 2-ftor-ara-AMF it is quickly dephosphorylated in an organism to nucleoside 2-ftor-ara-A. After single intravenous infusion within 30 min. the maximum concentration in plasma (Cmax) 2 Ftor-ara-A makes 3,5-3,7 µmol/l and is reached by the end of infusion. After five administrations of drug moderate increase in Cmax to 4,4-4,8 µmol/l by the end of infusion comes to light. At the same time cumulation 2-ftor-ara-A after several cycles of therapy can be insignificant. Communication with proteins of a blood plasma is insignificant.
 
After the end of infusion three-phase decrease in concentration with an elimination half-life (T1/2) of an initial phase of 5 min., T1/2 of an intermediate phase of 1-2 h and T1/2 of a terminal phase - about 20 h is observed.
 
Studying of pharmacokinetics 2-ftor-ara-A showed, that the general plasma clearance averages 79±40 ml/min./sq.m (2,2±1,2 ml/min.), and the average volume of distribution - 83±55 l/sq.m (2,4±1,61 l/kg). The obtained data indicate high individual variability. After intravenous (in/in) introductions concentration 2-ftor-ara-A in plasma and the area under a curve "concentration time" (AUC) increase in linear dependence on a dose whereas T1/2, the plasma clearance and volumes of distribution remain constants regardless of a dose.
 
It is removed preferential by kidneys (40-60% of the dose entered intravenously). 2-ftor-ara-A it is actively transported in leukemic cells where it refosforilirutsya to monophosphate and partially to di - and triphosphate. Triphosphate (2-ftor-ara-ATF) is the main intracellular metabolite and the only metabolite having cytotoxic activity. The maximum concentration of 2-ftor-ara-ATF in tumor cells was observed on average in 4 hours, at the same time considerable fluctuations of average peak concentration were noted (on average about 20 µmol/l). Concentration of 2-ftor-ara-ATF in tumor cells was also much higher, than its maximum concentration in plasma that indicates cumulation of substance in tumor cells. 2-ftor-ara-ATF T1/2 makes 15-23 hours of target cells. Accurate correlation between pharmacokinetics 2-ftor-ara-A and medical effect of drug at oncological patients is not revealed, however the frequency of a neutropenia and change of a hematocrit indicate the dozozavisimy nature of cytotoxic action (in the form of oppression of a hemogenesis) a fludarabin of phosphate.
 
At persons with reduced function of kidneys reduction of the general clearance of drug was observed that indicates dose declines the need.

Indications to use:

- chronic V-cellular lymphoid leukosis (HLL);
 
- nekhodzhkinsky lymphoma of low degree of a zlokachestvennost (NHL of NZ).

Route of administration and doses:

Флугарду® it is necessary to enter only intravenously, at the same time it is necessary to avoid its accidental extravasated hit.
 
The recommended dose of a fludarabin of phosphate makes 25 mg/sq.m of a body surface in/in within 5 days each 28 days once a day.
 
Contents of each bottle should be dissolved in 2 ml of water for injections. 1 ml of the prepared solution contains 25 mg of a fludarabin of phosphate. The required dose (calculated proceeding from a body surface of the patient) is gathered in the syringe. Then this dose dissolve 0,9% of solution of sodium chloride in 10 ml and enter intravenously struyno or dissolve 0,9% of solution of sodium chloride in 100 ml and enter intravenously kapelno approximately within 30 minutes.
 
Duration of treatment depends on effect and portability of drug.
 
Sick HLL Flugarda® it has to be appointed before achievement of the maximum answer (full or partial remission, usually - 6 cycles) then treatment has to be stopped.
 
At sick NHL of NZ treatment of Flugardoy® is recommended to be carried out before achievement of the maximum answer (full or partial remission). After achievement of the greatest effect it is necessary to discuss need of carrying out two cycles of consolidation. According to clinical tests at NHL of NZ, most of patients received no more than 8 cycles of treatment.
 
Patients with an abnormal liver function. Data on efficiency and safety of a fludarabin at patients with abnormal liver functions are limited. To patients of this group флударабин appoint with care after careful assessment of a ratio risk/advantage. Treatment of these patients has to be carried out under fixed observation. In case of need it is necessary to lower a dose of drug or to cancel treatment.
 
Patients with a renal failure. At patients with possible renal failures and at persons 70 years are more senior determination of clearance of creatinine is necessary. At clearance of creatinine from 30 to 70 ml/min. the dose has to be reduced to 50%, constant hematologic control is necessary for assessment of toxicity. Treatment of Flugardoy® is contraindicated at clearance of creatinine <30 ml/min.

Features of use:

Treatment fludarabiny should be carried out under observation of the doctor having experience of use of cytotoxic means.
 
At therapy fludarabiny it is recommended to estimate periodically indicators of peripheral blood for detection of anemia, a neutropenia and thrombocytopenia, to carefully control concentration of creatinine in blood serum and clearance of creatinine, and also to carry out careful monitoring of the TsNS function for the purpose of early detection of possible neurologic frustration.
 
Oppression of marrow usually has reversible character. At therapy fludarabiny the greatest decrease in number of neutrophils is on average observed for the 13th day (3-25 day) from an initiation of treatment, thrombocytes - on average for the 16th day (2-32 day). Miyelosupressiya can be expressed and have cumulative character. Several cases of a hypoplasia or an aplasia of marrow at the adults who are shown a pancytopenia, sometimes from the death were described. Duration of clinically significant pancytopenia made from 2 months to 1 year. These episodes were revealed as at pretreated, and not treated patients.
 
Performing preventive therapy is recommended to patients with the increased risk of development of opportunistic infections. Against the background of therapy fludarabiny development of the serious opportunistic infections in certain cases leading to death was noted.
 
It is necessary to show care at purpose of a fludarabin to patients to whom change of the hemopoietic stem cells is planned further.
 
At transfusion of unirradiated blood to the patients receiving treatment fludarabiny reaction development "a transplant against the owner" was observed (reaction of transplantirovanny immunocompetent lymphocytes against the owner). It was reported about the high frequency of deaths owing to this reaction. In this regard to patients who need hemotransfusions and who receive or received treatment fludarabiny, it is necessary to transfuse only the irradiated blood.
 
The syndrome of a lysis of a tumor arising at treatment fludarabiny was observed at patients from HLL having big tumoral weight. As флударабин can render medical effect on the first week of therapy, it is necessary to take precautionary measures at patients with probable risk of development of this complication.
 
Regardless of existence or lack of autoimmune processes in the anamnesis, and also from results of test of Koombs, there is a risk of emergence of life-threatening autoimmune reactions (autoimmune hemolitic anemia, autoimmune thrombocytopenia, a Werlhof's disease, a pemphigus, Fischer-Evans's syndrome) in time or after treatment fludarabiny. Repeated hemolitic process after treatment resuming fludarabiny is possible. In case of development of hemolysis the therapy termination is recommended. Treatment at hemolitic anemia consists in a transfusion of the irradiated blood and introduction of glucocorticosteroids.
 
The men and women having sex have to apply reliable methods of contraception in time (and within 6 months after the termination) treatments fludarabiny. In time and after treatment fludarabiny it is necessary to avoid vaccination by live vaccines.
 
Most of patients, insensitive to a fludarabin, are also insensitive to a hlorambutsil.
 
It is necessary to follow rules of use and destruction of cytostatic means. To avoid contact with solution! In case of hit of solution on skin or mucous membranes these sites should be washed out carefully water with soap. In case of hit in eyes it is necessary to wash out carefully eyes a large amount of water.

Influence on ability to manage vehicles and mechanisms. Some side effects of a fludarabin can negatively influence ability to drive the car and to be engaged in potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

Frequency of side effects is specified below according to the following gradation: very often (more than 10%), it is frequent (more than 1%, but less than 10%), infrequently (more than 0,1%, but less than 1%), is rare (more than 0,01%, but less than 0,1%).
 
From bodies of a hemopoiesis: very often - a neutropenia, thrombocytopenia and anemia; often - a miyelosupressiya.
 
From immune system: infrequently - autoimmune disorders (including autoimmune hemolitic anemia, a Werlhof's disease, a pemphigus, Fischer-Evans's syndrome, the acquired hemophilia), allergic reactions.
 
From the alimentary system: very often - nausea, vomiting, diarrhea; often - anorexia, stomatitis, mukozit; infrequently - gastrointestinal bleedings, change of activity of enzymes of a liver and pancreas.
 
From a metabolism: infrequently - as a result of a lysis of a tumor the hyperuricemia, a hyperphosphatemia, a hypocalcemia, a metabolic acidosis, a hyperpotassemia, a hamaturia, an uratny crystalluria and a renal failure can develop.

From a nervous system: often - peripheral neuropathy, infrequently - confusion of consciousness; seldom - the coma or excited state, epileptiform attacks.

From an organ of sight: often - a vision disorder. Neuritis or neuropathy of an optic nerve, a blindness were seldom observed.
 
From respiratory system: very often - cough; infrequently - short wind, pulmonary fibrosis, a pneumonitis.
 
From cardiovascular system: seldom - heart failure, arrhythmias.
 
From an urinary system: seldom - hemorrhagic cystitis.
 
From skin and skin appendages: often - skin rash, it is rare - Stephens-Johnson's syndrome or a toxic epidermal necrolysis (Lyell's disease), It was reported about exceptional cases of strengthening of growth of the available carcinoma cutaneum, and also development of a carcinoma cutaneum in time or after treatment fludarabiny.

Others: very often - fervescence, increased fatigue, weakness, accession of secondary infections / opportunistic infections (for example, reactivation of latent viruses, including viruses of herpes and Epstein-Barre, a progressive multifocal leukoencephalopathy, pneumonia); often - a fever, an indisposition, peripheral hypostases; seldom - the limfoproliferativny disturbances (connected with Epstein-Barre's virus).
 
At the patients receiving флударабин to after or along with the alkylating cytotoxic means or radiotheraphy, the miyelodisplastichesky syndrome the MDS/acute myeloid leukosis (AML) was in rare instances observed.

Interaction with other medicines:

Use of a fludarabin in a combination with pentostatiny for treatment of a refractory chronic lymphoid leukosis often led to a lethal outcome because of high pulmonary toxicity.
 
The therapeutic effectiveness of a fludarabin can decrease at simultaneous use with Dipiridamolum.
 
At use of a combination of a fludarabin and Cytarabinum pharmacokinetic interaction was observed. At combined use of Cytarabinum with fludarabiny higher intracellular maximum concentration and the area under a curve "time concentration" (AUC) of a metabolite of Cytarabinum - an arabinozil of a tsitozintrifosfat are shown. Plasma concentration of Cytarabinum and removal of an arabinozil of a tsitozintrifosfat did not change.
 
Pharmaceutical interaction. Solution of a fludarabin for in/in uses cannot be mixed with other drugs.

Contraindications:

- Hypersensitivity to a fludarabin or other components of drug;
 
- renal failure (clearance of creatinine <30 ml/min.);
 
- dekompensirovanny hemolitic anemia;
 
- pregnancy and period of feeding by a breast.

With care. After careful assessment of a ratio risk/advantage флударабин it is necessary to apply at the weakened patients, at the expressed marrow depression of function (thrombocytopenia, anemia and/or a granulocytopenia), at renal (KK of 30-70 ml/min.) or a liver failure, an immunodeficiency, opportunistic infections in the anamnesis, at patients 75 years are more senior.
 
The available data on safety and efficiency of a fludarabin at children do not allow to make unambiguous recommendations of its relative use in pediatric practice.

Overdose:

At overdose of a fludarabin development of irreversible changes from the central nervous system is possible, a late blindness, a coma and a lethal outcome, and also development of a severe form of thrombocytopenia and a neutropenia owing to suppression of function of marrow. In case of the menacing symptoms drug it is necessary to cancel and carry out a maintenance therapy immediately. The specific antidote is not known.

Storage conditions:

To store in the dry place protected from light at a temperature not above 30 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Lyophilisate for preparation of solution for intravenous administration, 50 mg. Packaging: on 50 mg of a fludarabin of phosphate in the bottles of colourless neutral glass which are hermetically corked by rubber bungs with a running in caps aluminum. On 1 or 5 bottles with the application instruction in a pack from a cardboard.