Флудара®

General characteristics. Structure:

With lyophilisate contains in each bottle

Active agent: fludarabina phosphate of 50 mg Excipients: Mannitolum, sodium hydroxide.

1 tablet contains

Active agent: fludarabina phosphate of 10 mg.
Excipients: cellulose microcrystallic, lactoses monohydrate, karmelloza of sodium (sodium carboxymethylcellulose), silicon dioxide colloid, magnesium stearate, gipromelloz (gidroksipropilmetiltsellyuloz), talc, titanium dioxide, gland (II) oxide, gland (III) oxide.

Description. The white lyophilized powder
Tablets of a kapsulovidny form, film coated, from salmoncolored till pink color with an engraving of "LN" in the correct hexagon on one of the parties.

Pharmacological properties:

Pharmacodynamics. Fludara contains a fludarabin phosphate, the fluorinated nucleotide analog of the antiviral agent of a vidarabin, 9-R-0-arabinofuranoziladenina (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 intracellular is 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 synthesis disturbance
DNA. Besides, the RNA polymerase of II with the subsequent decrease in proteinaceous synthesis is partially inhibited.

Pharmacokinetics. Accurate correlation between pharmacokinetics of a fludarabin and its medical effect at oncological patients, at the same time the frequency of detection of a neutropenia and change of a hematocrit - a dozozavisim was not revealed.
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 removed preferential by kidneys (from 40 to 60% of the dose entered intravenously).
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 cells was 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.

Indications to use:

Intravenous administration
• V-cellular chronic lymphoid leukosis (HLL)
• Nekhodzhkinsky lymphoma of low degree of a zlokachestvennost (NHL of NZ) Intake
• V-cellular chronic lymphoid leukosis (HLL)
• Nekhodzhkinsky lymphoma of low degree of a zlokachestvennost (NHL of NZ)
• Follicular V-cellular lymphoma
• Lymphoma from cells of a mantle zone

Route of administration and doses:

Intravenous administration
Fludara should be entered only intravenously. There were no messages on emergence of the expressed local side reactions at Fludara's introduction ekstravazalno. However it is necessary to avoid accidental extravasated hit of drug.
The recommended dose of a fludarabin of phosphate makes 25 mg/sq.m of a body surface daily within 5 days each 28 days at intravenous administration.
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 of chloride in 10 ml and enter intravenously struyno or dissolve 0,9% of solution of sodium of chloride in 100 ml and enter intravenously kapelno approximately within 30 minutes.
Tablets
The recommended dose for intake makes 40 mg/sq.m of a body surface daily within 5 days each 28 days. A pill can be taken as next the heart, and along with meal. It is necessary to swallow of tablets entirely (not to chew, not to break), washing down with water.
Treatment duration
Duration of treatment depends on effect and portability of drug. Sick HLL Fludara 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 by Fludara 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 consider 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.
Children
Efficiency and safety of use of Fludara for children are not established.
Renal failure
At clearance of creatinine from 30 to 70 ml/min. it is necessary to reduce a dose by 50%. When performing therapy at these patients constant hematologic control is necessary.

Features of use:

Treatment by Fludara should be carried out under observation of the doctor having experience of use of cytotoxic means.
At therapy by Fludara 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 of solid tumors by Fludara 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 (2-32 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.
Effects of prolonged use of Fludara on the central nervous system are unknown. However, in some researches it was shown that at rather long use (to 26 courses of therapy) Fludara is well had by patients.
Against the background of therapy by Fludara development of the serious opportunistic infections in certain cases leading to death was noted. Performing preventive therapy is recommended to patients with the increased risk of development of opportunistic infections.
Regardless of existence or 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 by Fludara was described. At most of patients with hemolitic anemia the hemolysis recurrence after provocative test with Fludara was celebrated. The patients receiving treatment by Fludara have to be observed carefully regarding emergence of symptoms of hemolitic anemia. In case of development of hemolysis the termination of therapy by Fludara 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 getting Fludara to after or along with
the alkylating cytotoxic means or radiotheraphy, were observed a miyelodisplastichesky syndrome (MDS) / acute myeloid leukosis (AML). At monotherapy of Fludary MDS/OML were not observed.
The reaction "a transplant against the owner" (reaction of transfuziruyemy immunocompetent lymphocytes against the owner) resulting from hemotransfusions it was observed after transfusion of unirradiated blood by the patient receiving treatment by Fludara. It was reported about the high frequency of deaths, as a result of this disease. In this regard to patients who need hemotransfusions and who receive or received treatment by Fludara, it is necessary to transfuse only the irradiated blood.
As Fludara 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 Fludara's use for patients of advanced age (75 years are more senior) Fludara at this age has to be appointed with care.
It must be kept in mind that patients resistant to therapy by Fludara in most cases show resistance and to a hlorambutsil.
Fertile women and men have to use reliable methods of contraception in time and not less than 6 months after the end of therapy.
In time and after treatment by Fludara it is necessary to avoid vaccination by live vaccines.
At the address with fludarabiny all instructions accepted for use and destruction of cytotoxic drugs have to be observed. It is necessary to avoid drug inhalation. Use of goggles and latex gloves is recommended. 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. Pregnant women are forbidden to work with Fludara.
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.

Side effects:

Frequency of the undesirable phenomena is specified on the basis of these clinical trials, irrespective of relationship of cause and effect using Fludara, according to the following gradation: very often (> 10%), it is frequent (<10%-> 1%), infrequently (<1%-> 0,1%), is rare (<0,1%-> 0,01%).
Infections: very often - accession of secondary infections / opportunistic infections (as, for example, reactivation of latent viruses, including, viruses of herpes and Epstein-Burra, a progressive multifocal leukoencephalopathy), pneumonia; seldom - the limfoproliferativny disturbances (connected with Epstein-Burra's virus). 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 pempigus, Evans's syndrome, the acquired hemophilia).
From system of digestion: very often - nausea, vomiting, diarrhea; often - anorexia, stomatitis, mukozit; infrequently - gastrointestinal bleedings, disturbance of indicators of enzymes of a liver and pancreas.
Metabolism disturbances: 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 - excitement, spasms, a coma.
From organs of sight: often - vision disorders; seldom - an optic neuritis, visual neuropathy and a blindness.
From respiratory system: very often - cough; infrequently - short wind, pulmonary fibrosis, a pneumonitis
From cardiovascular system: seldom - heart failure, arrhythmias. From urinogenital system: seldom - hemorrhagic cystitis.
From skin and skin appendages: 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 available carcinoma cutaneum, and also development of a carcinoma cutaneum in time or after treatment by Fludara.
Others: very often - fervescence, increased fatigue, weakness, is frequent - a fever, an indisposition, hypostases.
At the patients getting Fludara 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:

Fludara's use in a combination with pentostatiny (dezoksikoformitsiny) for treatment of a chronic lymphoid leukosis (HLL) often led to a lethal outcome because of high pulmonary toxicity. Therefore Fludara's use in a combination with pentostatiny is not recommended.
Dipiridamolum or other inhibitors of the return capture of adenosine can reduce a therapeutic effectiveness of Fludara.
Fludara's solution for intravenous use cannot be mixed with other drugs.

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.

With care.
Fludara has to be appointed with care after careful assessment of a ratio risk/advantage the patient in the weakened state, the patient with the expressed marrow depression of function (thrombocytopenia, anemia and/or a granulotsiopeniya), an immunodeficiency or with opportunistic infections in the anamnesis, to children and patients 75 years, the patient with a renal failure are more senior.

Overdose:

High doses of Fludara cause the irreversible changes in the central nervous system including a blindness, a coma and death. At Fludara's use in doses by 4 times exceeding recommended (96 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 of high doses is also connected with development of the expressed thrombocytopenia and a neutropenia owing to suppression of function of marrow.
Specific antidotes at Fludara's overdose are unknown. Treatment consists in the termination of administration of drug and carrying out a maintenance therapy.

Storage conditions:

At a temperature not above 30 °C. To store in the place, unavailable to children. Period of validity. Lyophilisate for preparation of injection solution - 3 years.

The recovered solution has to be used no later than 8 hours after preparation.
Tablets - 2 years. Not to apply after the period of validity specified on packaging!

Issue conditions:

According to the recipe

Packaging:

Lyophilisate for preparation of solution for intravenous administration on 50 mg in the bottles corked with traffic jams, rolled by an aluminum cap with a color plastic cover. 5 bottles placed in pallets (cardboard inserts) together with the instruction place in a cardboard pack.
Tablets film coated on 10 mg. On 5 tablets in the blister from aluminum foil. 2, 3, 4 or 5 blisters place in a plastic case with the twisting cover. The case together with the application instruction is placed in a cardboard pack.