Флугарда®

General characteristics. Structure:

Active ingredient: 10 mg of a fludarabin of phosphate.
 
Excipients: lactoses monohydrate, starch prezhelatinizirovanny, кросповидон, the sodium stearylfumarating silicon dioxide colloid.
 
Cover: film covering (dye ferrous oxide red (Е 172), talc, dye ferrous oxide yellow (Е 172), gipromelloza, titanium dioxide (Е 171).

Pharmacological properties:

Pharmacodynamics. Флугарда® phosphate, the fluorinated nucleotide analog of the antiviral agent of a vidarabin, 9-β-D-арабинофуранозиладенина contains a fludarabin (ara-A) which is rather steady against deamination by an adenosinedeaminase. In a human body of a fludarabin phosphate is quickly dephosphorylated to 2-ftor-ara-A which, being taken cells, then is intracellularly phosphorylated to active triphosphate (2-ftor-ara-ATF). This metabolite inhibits RNA-reductase, a DNA polymerase (an alpha, the delta and an upsilon), DNK-praymazu and DNA-ligase that leads to DNA synthesis disturbance. Besides, the RNA polymerase of II with the subsequent decrease in proteinaceous synthesis is partially inhibited. 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. Ne it was revealed accurate correlation between pharmacokinetics of a fludarabin and its medical effect at oncological patients, at the same time the frequency of detection of neutropenias and change of a hematocrit-dozozavisima.
 
Fludarabina phosphate (2-ftor-ara-AMF) is a water-soluble predecessor of a fludarabin (2-ftor-ara-A), in a human body 2-ftor-ara-AMF is quickly and completely dephosphorylated to nucleoside 2-ftor-ara-A. Communication with proteins of a blood plasma - insignificant.
 
2-ftor-ara-A it is actively transported in leukemic cells then it refosforilirutsya to monophosphate and partially to di - and triphosphate. Triphosphate (2-ftor-ara-ATF) is the main intracellular metabolite and the only thing from the known metabolites having cytotoxic activity. Concentration of 2 ftor-ara-ATF in leukemic staff-woods was also much higher, than its maximum concentration in plasma that indicates cumulation of substance in tumor cells. The 2-ftor-ara-ATF elimination half-life from target cells averages from 15 to 23 hours. After intake the maximum concentration (Cmax) (20-30% of the concentration defined by the end of intravenous infusion) in blood is observed in 1-2 h. Bioavailability makes 50-65%.

Food slightly (less than 10%) increases the area under a curve and reduces Tmax (time of achievement of the maximum concentration) and Cmax, does not change an elimination half-life.

At a chronic renal failure its clearance decreases.

Indications to use:

- V-cellular chronic lymphoid leukosis (HLL);
 
- nekhodzhkinsky lymphoma of low degree of a zlokachestvennost (NHL of NSZ);
 
- follicular V-cellular lymphoma;
 
- lymphoma from cells of a mantle zone.

Route of administration and doses:

Features of use:

Pregnancy and lactation. Use for pregnant women and in the period of a lactation contraindicated. Also pregnant women are forbidden to work with drug.

Treatment by the drug Flugarda® should be carried out under observation of the doctor having experience of use of cytotoxic means.
 
At therapy the drug Flugarda® recommends 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 has usually reversible character. At therapy fludarabiny solid tumors at adults 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 (2-23 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. Effects of prolonged use of a fludarabin on the central nervous system are unknown. At therapy the drug Flugarda® recommends to make control of indicators of the central nervous system, in connection with a possible neurotoxicity of drug which is described at therapy fludarabiny in high doses. Within post-registration experience of use of a fludarabin cases of development of a leukoencephalopathy, an acute toxic leukoencephalopathy and a syndrome of a reversible back leukoencephalopathy are registered. However in some researches it was shown that at rather long use (to 26 courses of therapy) the fludarabina is well transferred by patients.
 
The pas a therapy background fludarabiny was noted development of the serious opportunistic infections, in certain cases, leading to death. Performing preventive therapy is recommended to patients with the increased risk of development of opportunistic infections.
 
Regardless of existence at lack of autoimmune processes in the anamnesis, and also results of test of Koombs emergence life-threatening, and sometimes and deadly autoimmune reactions (autoimmune hemolitic anemia, autoimmune thrombocytopenia, a Werlhof's disease, a pempigus, Evans's syndrome) in time or after treatment fludarabiny was described. At most of patients with hemolitic anemia the hemolysis recurrence after provocative test with fludarabiny was celebrated.
 
The manumissions receiving treatment fludarabiny have to be observed carefully regarding emergence of symptoms of hemolitic anemia. In case of development of hemolysis the therapy termination fludarabiny is recommended. The most widespread medical actions at hemolitic anemia are transfusions of the irradiated blood and therapy by glucocorticosteroids.
 
In rare instances at the patients receiving флударабин to after or along with the alkylating cytostatic means, inhibitors of topoisomerase or radiotheraphy, were observed наблюдись a miyelodisplastichesky syndrome (MDS) / acute myeloid leukosis (AML). At monotherapy fludarabiny MDS/OML were not observed. The reaction "a transplant against the owner" (reaction of transfuziruyemy immunocompetent lymphocytes bend the owner) resulting from haemo transfusions was observed after transfusion of unirradiated blood by the patient receiving treatment fludarabiny. It was reported about the high frequency of deaths, as a result of this disease. In this regard to patients who need haemo transfusions and who receive or received treatment by drug fludarabiny, it is necessary to transfuse only the irradiated blood.
 
It was reported about isolated cases development of a carcinoma cutaneum, and also strengthening growth of already available carcinoma cutaneum, in time or after treatment fludarabiny.
 
As Flugarda® can cause a lysis of a tumor on the first week of therapy, has to be careful at treatment of patients with risk of development of this syndrome (especially with a big tumoral weight).
 
In connection with the insufficient number of clinical data on use of a fludarabin for patients of advanced age (75 years are more senior), флударабин at this age it has to be applied with care.
 
It must be kept in mind that patients resistant to therapy fludarabiny in most cases show resistance and to a hlorambutsil.
 
Fertile women and men have to use case methods of contraception during treatment and not less than 6 months after the end of therapy.
 
In time and after treatment fludarabiny it is necessary to avoid vaccination by live vaccines.
 
Precautionary measures at use. At the address with fludarabiny have to be observed instruction weight, accepted for use and destruction of cytotoxic drugs. It is necessary to avoid drug inhalation. It is recommended use of goggles and latex gloves. In case of hit of solution on skin or mucous membranes lie 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.

Pregnant women have enough to work with fludarabiny.

Influence on ability to manage vehicles and mechanisms. Some side effects of drug, such as the increased fatigue, weakness, vision disorders can negatively influence ability of driving and performance of potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions. At emergence of the described undesirable phenomena it is necessary to refrain from performance of the specified types of activity.

Side effects:

Frequency of the undesirable phenomena is specified on the basis of these clinical trials, irrespective of relationship of cause and effect using a fludarabin, according to the following gradation: very often (≥10%), it is frequent (<10% - ≥1%), infrequently (<1% - ≥0,1%), is rare (<0,1% - ≥0,01%), frequency is unknown.
 
Infectious and parasitic diseases. Very often - accession of secondary infections / opportunistic infections (for example, reactivation of latent viruses, including viruses herpes and Epstein-Barre, the progressing multifocal leukoencephalopathy), pneumonia; seldom - the limfoproliferativny disturbances (connected е by Epstein-Barre's virus).
 
Disturbances from blood and lymphatic system. Very often - a neutropenia, thrombocytopenia and anemia; often - a miyelosupressiya.
 
Disturbances from immune system. Infrequently - autoimmune disorders (in т.ч, autoimmune hemolitic anemia, a Werlhof's disease, a pempigus, Evans's syndrome, the acquired hemophilia).
 
Disturbances from digestive tract. Very often - nausea, vomiting, diarrhea; often - anorexia, stomatitis, mukozit; infrequently - gastrointestinal bleedings, change of activity of enzymes of a liver and pancreas.
 
Disturbances from a metabolism and food. 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.
 
Disturbances from a nervous system. Often - peripheral neuropathy; infrequently - confusion of consciousness; seldom - excitement, spasms, a coma.
 
Disturbances from an organ of sight. Often - a vision disorder; seldom - an optic neuritis, neuropathy of an optic nerve and a blindness.
 
Disturbances from respiratory system, bodies of a thorax and a mediastinum. Very often - cough; infrequently - short wind, pulmonary fibrosis, a pneumonitis.
 
Disturbances from heart. Seldom - heart failure, arrhythmias.
 
Disturbances from kidneys and urinary tract. Seldom - hemorrhagic cystitis.
 
Disturbances from skin and hypodermic fabrics. Often - skin rash; seldom - Stephens-Johnson's syndrome, a toxic epidermal necrolysis (Lyell's disease). It was reported about exceptional cases of strengthening of growth of the having carcinoma cutaneum, and also development of a carcinoma cutaneum in time or after treatment fludarabiny.
 
The general frustration and disturbances in an injection site. Very often - з ate temperature increase, increased fatigue, weakness; often - a fever, an indisposition, hypostases.
 
The high-quality, malignant and not specified new growths (including cysts and polyps). At the patients receiving флударабин to after or at the same time alkylating antistatic means, inhibitors of topoisomerase or radiotheraphy, were in rare instances observed a miyelodisplastichesky syndrome (MDS) / acute myeloid leukosis (AML).
 
Post-registration data. Disturbances from a nervous system. Frequency is unknown - a leukoencephalopathy, an acute toxic leukoencephalopathy, the syndrome of a reversible back leukoencephalopathy (SRBL).
 
Disturbances from vessels. Frequency is unknown - bleedings (including cerebral bleeding, pulmonary bleeding).

Interaction with other medicines:

Use of a fludarabin in a combination with pentostatiny (dezoksikoformitsiny) for treatment of a refractory chronic lymphoid leukosis (HLL) often led to a lethal outcome because of high pulmonary toxicity therefore use of the drug Flugarda® in a combination with pentostatiny is not recommended.
 
Dipiridamolum or other inhibitors of the return capture of adenosine can reduce a therapeutic effectiveness of a fludarabin.
 
At treatment the combination of a fludarabin and Cytarabinum at patients with a chronic lymphoid leukosis and an acute myeloid leukosis observed pharmacokinetic interaction. At combined use of Cytarabinum with fludarabiny higher intracellular peak concentration and intracellular 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.

Contraindications:

- Hypersensitivity to a fludarabin or other components of drug;
 
- a renal failure with clearance of creatinine <30 ml/min.;
 
- dekompensirovanny hemolitic anemia;
 
- pregnancy and period of feeding by a breast;
 
- children's age (lack of sufficient clinical data).

With care. Флугарда® the risk/advantage the patient in the weakened state, the patient with the expressed marrow depression of function (thrombocytopenia, anemia, and/or a granulocytopenia), an immunodeficiency or with opportunistic infections in the anamnesis has to be applied with care after careful assessment of a ratio, the patient 75 years, the patient with a renal failure (clearance of creatinine - 30-70 ml/min.), the patient with a liver failure, the patient with deficit of lactase, a lactose intolerance, a syndrome of glyukozo-galaktozny malabsorption are more senior.

Overdose:

High doses of a fludarabin cause the irreversible changes in the central nervous system including a blindness, a coma and death. Use of a fludarabin in the doses, by 4 times exceeding recommended (95 mg/sq.m/days within 5-7 days) the neurotoxicity was observed approximately at 36% of patients, at the same time symptoms of a neurotoxicity appeared for 21-60 day after introduction of the last dose.
 
Use in doses, the exceeding recommended, is also connected with development of the expressed thrombocytopenia and a neutropenia owing to suppression of function of marrow.
 
Specific antidotes at overdose of a fludarabin are unknown. Treatment consists in the termination of administration of drug and carrying out a maintenance therapy.

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 - 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 5 tablets in a blister strip packaging. On 2, 3, 4 or 5 blister strip packagings together with the application instruction in a pack from a cardboard.