Флидарин®

General characteristics. Structure:

Active ingredient: 10 mg of a fludarabin of phosphate.

Vspmoatelny substances: алюмометасиликат magnesium, croscarmellose sodium, silicon dioxide colloid, magnesium stearate, лудипресс (lactoses monohydrate, K30 povidone, кросповидон).

Cover: Опадрай the II white 85F48105 (polyvinyl alcohol – 46,9%, talc – 17,4%, a macrogoal of 3350 - 23,6%, titanium dioxide – 12,1%).

Pharmacological properties:

Pharmacodynamics. The antineoplastic drug containing 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. Fludarabina phosphate is quickly dephosphorylated to       2-ftor-ara-A which, being taken cells, then is intracellularly phosphorylated dezoksitsitidinkinazy 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 owing to what DNA synthesis is oppressed. 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. Accurate correlation between pharmacokinetics of a fludarabin and its medical effect at oncological patients is not revealed, at the same time the frequency of detection of a neutropenia and changes of a hematocrit are dozozavisimy.

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

Distribution and metabolism: the fludarabina phosphate (2-ftor-ara-AMF) is a water-soluble predecessor of a fludarabin, in a human body 2-ftor-ara-AMF is quickly and completely dephosphorylated to nucleoside 2-ftor-ara-A. 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 is much higher, than its maximum concentration in plasma that indicates cumulation of substance in tumor cells.

Communication with proteins of a blood plasma insignificant. Bioavailability makes 50-65%.

Removal: 2-ftor-ara-A it is removed preferential by kidneys. The 2-ftor-ara-ATF elimination half-life from target cells averages from 15 to 23 hours.

Pharmacokinetics at separate groups of patients: patients with renal failures

At a chronic renal failure clearance 2-ftor-ara-A decreases.

Indications to use:

• V-cellular chronic lymphoid leukosis (HLL) (as therapy of the 1st line). Therapy by the drug Flidarin® as therapy of the 1st line can be begun only at patients with the progressing disease (a stage With on classification of Binet or III/IV stages on Rai classification), or at stages А/В on classification of Binet or I/II stages on Rai classification when symptoms and signs of progressing of a disease are observed.
• V-cellular chronic lymphoid leukosis (at patients, which rezistentna to therapy by the alkylating drugs or at whom progressing of a disease in time or after use of, at least, one standard scheme containing the alkylating drugs is noted).
• 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:

Treatment fludarabiny should be carried out under observation of the doctor having experience of use of antineoplastic therapy. Drug is appointed only the adult. Intake. Drug can be accepted as on an empty stomach, and along with meal. Tablets should be swallowed entirely (without chewing and without breaking), washing down with water.

The recommended dose for intake makes 40 mg/sq.m of surface area of a body daily, within 5 days, each 28 days.

Calculation of quantity of tablets depending on body surface area.

- Body Surface Area (BSA), sq.m: 0,75 - 0,88; the daily dose calculated depending on PPT, mg/days: 30 – 35; quantity of tablets in days: 3 (30 mg).

- Body Surface Area (BSA), sq.m: 0,89 - 1,13; the daily dose calculated depending on PPT, mg/days: 36 – 45; quantity of tablets in days: 4 (40 mg).

- Body Surface Area (BSA), sq.m: 1,14 - 1,38; the daily dose calculated depending on PPT, mg/days: 46 – 55; quantity of tablets in days: 5 (50 mg).

- Body Surface Area (BSA), sq.m: 1,39 - 1,63; the daily dose calculated depending on PPT, mg/days: 56 – 65; quantity of tablets in days: 6 (60 mg).

- Body Surface Area (BSA), sq.m: 1,64 - 1,88; the daily dose calculated depending on PPT, mg/days: 66 – 75; quantity of tablets in days: 7 (70 mg).

- Body Surface Area (BSA), sq.m: 1,89 - 2,13; the daily dose calculated depending on PPT, mg/days: 76 – 85; quantity of tablets in days: 8 (80 mg).

- Body Surface Area (BSA), sq.m: 2,14 - 2,38; The daily dose Calculated depending on PPT, mg/days: 86 – 95; quantity of tablets in days: 9 (90 mg).

- Body Surface Area (BSA), sq.m: 2,39 - 2,50; the daily dose calculated depending on PPT, mg/days: 96 – 100; quantity of tablets in days: 10 (100 mg).

Duration of treatment depends on efficiency and portability of drug. At HLL флударабин it is necessary to apply before achievement of the maximum answer (full or partial remission, usually – 6 cycles) then treatment has to be stopped.

At NHL of NZ treatment fludarabiny 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. The general duration of treatment usually makes no more than 8 cycles of therapy. Dose adjustment depending on quantity of uniform elements of blood

The patients receiving treatment fludarabiny have to undergo regularly careful inspection on existence of hematologic toxicity. If before the subsequent cycle of therapy the quantity of uniform elements of blood at the patient is lowered and there are bases to believe about existence of the miyelosupressiya connected with treatment, the planned cycle of treatment has to be postponed until recovery of quantity of granulocytes higher than 1.0 x 10 9/l and quantities of thrombocytes are higher than 100 x 109/l. The subsequent cycle of therapy can be postponed a maximum for two weeks. If the quantity of granulocytes and thrombocytes was not recovered after these two weeks, the dose of drug has to be reduced according to the scheme offered below.

- At quantity of granulocytes 0,5-1,0 and/or thrombocytes 50-100 [109/l] dose have to make 30 mg/sq.m/days.

- At quantity of granulocytes <0,5 and/or thrombocytes <50 [109/l] dose have to make 20 mg/sq.m/days.

It is not necessary to reduce a drug dose if thrombocytopenia is connected with a disease. If the condition of the patient does not change after 2 weeks of treatment, very small degree of hematologic toxicity will not come to light or will come to light, then careful dose adjustment with increase in a dose of a fludarabin in the subsequent cycles of treatment can be considered.

Patients with renal failures. At clearance of creatinine from 30 to 70 ml/min. the dose of drug needs to be reduced by 50%. When performing therapy at these patients constant hematologic control is necessary for toxicity assessment. At clearance of creatinine <30 ml/min. use of a fludarabin is contraindicated.

Patients with abnormal liver functions. Data on use of a fludarabin for patients with an abnormal liver function are absent. It is necessary to be careful at purpose of drug to this group of patients. 

Features of use:

Use at pregnancy and during breastfeeding. Drug is contraindicated for use at pregnancy and during breastfeeding.

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 a blood plasma and clearance of creatinine, and also to carry out careful monitoring of function of the central nervous system (CNS) for the purpose of early detection of possible neurologic frustration.

Neurotoxicity. When using high doses in researches for the purpose of definition of optimum doses at patients with an acute lymphoid leukosis, use of a fludarabin was connected with development of heavy neurologic symptoms, including a blindness, a coma and death. These symptoms developed within from 21 to 60 days after use of the last dose and were observed approximately at 36% of patients at intravenous use of a fludarabin in doses, approximately by 4 times exceeding recommended (96 mg/sq.m of a surface bodies/days within 5-7 days). At the patients accepting флударабин in the range of the doses recommended for treatment of a chronic lymphoid leukosis and a nekhodzhkinsky lymphoma of low degree of a zlokachestvennost, heavy toxic symptoms from TsNS are observed seldom (a coma, excitement and spasms) or infrequently (confusion of consciousness).

Influence of prolonged use of a fludarabin on TsNS is unknown. However it was shown what at rather long use (to 26 courses of therapy) флударабин is well transferred by patients. It is necessary to watch patients attentively for identification of neurologic symptoms.

Use of a fludarabin can be connected with development of a leukoencephalopathy, acute toxic leukoencephalopathy or syndrome of a reversible back leukoencephalopathy. These diseases can develop:
- at use in the recommended doses:
1. when флударабин use is applied after or in a combination with drugs,
whom also leads to development of a leukoencephalopathy, acute toxic
leukoencephalopathies or SOZL;
2. radiation or general (total) irradiation of all body, transplantation
hemopoietic cells, reaction "transplant against the owner", renal
insufficiency or hepatic encephalopathy.
- at use in the doses exceeding the recommended doses.

Symptoms of a leukoencephalopathy, acute toxic leukoencephalopathy or SOZL can include a headache, nausea and vomiting, spasms, visual disturbances (such as sight loss), sensitivity disturbance, focal neurologic symptomatology, and also an optic neuritis and a papillitis, confusion of consciousness, drowsiness, agitation, a paraparesis / квадропарез, a spasticity and an incontience.

The leukoencephalopathy, acute toxic leukoencephalopathy and SOZL can be irreversible, zhizneugrozhayushchy or fatal. At suspicion on a leukoencephalopathy, an acute toxic leukoencephalopathy or SOZL treatment fludarabiny has to be stopped. Patients have to be under observation of medical personnel. Patients need to make a brain tomography, MRT is preferable. If the diagnosis is confirmed, then therapy fludarabiny has to be stopped forever.

Patients in the weakened state. At patients in the weakened state флударабин it is necessary to apply with care and after careful assessment of a ratio risk/advantage. It is especially important for patients with heavy dysfunctions of marrow (thrombocytopenia, anemia and/or a granulocytopenia), an immunodeficiency or opportunistic infections in the anamnesis.

Against the background of therapy fludarabiny 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.

Miyelosupressiya. At the patients receiving therapy fludarabiny heavy oppression of function of marrow, the expressed anemia, thrombocytopenia and a neutropenia can be noted. At therapy fludarabiny solid tumors at adults the greatest decrease in quantity of neutrophils is on average observed for the 13th day (the 3-25th day) from an initiation of treatment, thrombocytes – on average for the 16th day (the 2-32nd day). Miyelosupressiya can be expressed and have cumulative character. Though the miyelosupressiya induced by chemotherapy often has reversible character, use of a fludarabin demands careful hematologic control.

Several cases of a hypoplasia or aplasia of marrow at the adults shown by a pancytopenia, sometimes from the death were described. Duration of clinically significant pancytopenia made from 2 months to 1 year. These episodes were revealed both at pretreated, and at not treated patients.

Progressing of a disease. Progressing of a disease and its transformation (for example, Richter's syndrome) are usually noted at patients with a chronic lymphoid leukosis.

Reaction "transplant against the owner". The reaction "a transplant against the owner" (reaction of transfuziruyemy immunocompetent lymphocytes against the owner) resulting from hemotransfusions is observed after transfusion of unirradiated components of blood to the patients receiving treatment fludarabiny. It is 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 fludarabiny, it is necessary to pour only the irradiated blood components.

Carcinoma cutaneum. At patients in time or after therapy fludarabiny deterioration or an aggravation of already existing tumoral damages of skin, and also development of new malignant new growths of skin can be noted.

Syndrome of a lysis of a tumor. As флударабин can cause a lysis of a tumor on the first week of therapy, it has to be careful at treatment of patients with risk of development of this syndrome (especially with a big tumoral weight).

Autoimmune diseases. 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 fludarabiny was described. At most of patients with hemolitic anemia the hemolysis recurrence after repeated use of a fludarabin is celebrated.

The patients 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.

Renal failures. There are limited clinical data on use of a fludarabin for treatment of patients with a renal failure (clearance of creatinine <70 ml/min.). The drug Flidarin® has to be used with care at patients with a renal failure. At patients with renal failures of moderate severity (clearance of creatinine of 30-70 ml/min.) the dose needs to be reduced by 50% and to make careful observation of patients. Treatment by the drug Flidarin® contraindicated, if clearance of creatinine <30 ml/min.

Elderly patients. 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 it is necessary to apply with care at this category of patients. At patients at the age of 65 years is also more senior, it is necessary to control clearance of creatinine prior to treatment.

Vaccination. In time and after treatment fludarabiny it is necessary to avoid vaccination by live vaccines.

Repeated course of treatment after initial therapy fludarabiny. It is necessary to avoid transition from initial therapy fludarabiny on hlorambutsit at the patients who did not answer therapy fludarabiny as patients, resistant to therapy fludarabiny, in most cases show resistance and to a hlorambutsil.

Other preventions. Women and men with the kept breeding potential have to use reliable methods of contraception during treatment and not less than 6 months after the end of therapy.

Rules of the address with fludarabiny. At the address with fludarabiny all instructions accepted for use and destruction of cytotoxic drugs have to be observed. 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, confusion of consciousness, a vision disorder can negatively influence ability to drive the car and to carry out 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:

The undesirable reactions given below are listed according to defeat of bodies and systems of bodies and occurrence frequency. Frequency of emergence of side reactions is estimated as follows: arising "it is very frequent" –> 10%; "often" –> 1% and <10%, "infrequently" –> 0,1% and <1%, is "rare" –> 0,01% and <0,1%, "is very rare" – <0,01%, including separate messages, "frequency is unknown".

Disturbances from blood and lymphatic system: very often – a neutropenia, thrombocytopenia and anemia; often – a miyelosupressiya.

Disturbances from immune system: infrequently – autoimmune diseases (including autoimmune hemolitic anemia, a Werlhof's disease, a pempigus, Evans's syndrome, the acquired hemophilia).

Disturbances from a metabolism and food: often – anorexia; infrequently – a hyperuricemia, a hyperphosphatemia, a hypocalcemia, a metabolic acidosis, a hyperpotassemia, a hamaturia, an uratny crystalluria (can develop as a result of a lysis of a tumor).

Disturbances from a nervous system: often – peripheral neuropathy; infrequently – confusion of consciousness; seldom – agitation, spasms, a coma; frequency is unknown – a leukoencephalopathy, an acute toxic leukoencephalopathy, the syndrome of a reversible back leukoencephalopathy (SRBL).

Disturbances from an organ of sight: often – vision disorders; seldom – an optic neuritis, visual neuropathy, a blindness.

Disturbances from heart: seldom – heart failure, arrhythmias.

Disturbances from vessels: frequency is unknown – bleedings (including cerebral bleeding, pulmonary bleeding).

Disturbances from respiratory system, bodies of a thorax and a mediastinum: very often – cough; infrequently – pulmonary toxicity (including short wind, pulmonary fibrosis, a pneumonitis).

Disturbances from digestive tract: very often – nausea, vomiting, diarrhea; often – stomatitis, mukozita; infrequently – gastrointestinal bleedings, an aberration of indicators of activity of enzymes of a pancreas.

Disturbances from a liver and biliary tract: infrequently – an aberration of indicators of activity of enzymes of a liver.

Disturbances from skin and hypodermic fabrics: often – skin rash; seldom – a carcinoma cutaneum, Stephens-Johnson's syndrome, a toxic epidermal necrolysis (Lyell's disease).

Disturbances from kidneys and urinary tract: seldom – hemorrhagic cystitis; infrequently – a renal failure (can develop as a result of a lysis of a tumor).

Infectious and parasitic diseases: very often – accession of consecutive/opportunistic infections (for example, reactivation of latent viral infections, including caused by the Herpes zoster virus and Epstein-Barre's virus, a progressive multifocal leukoencephalopathy), pneumonia; seldom – the limfoproliferativny disturbances (connected with Epstein-Barre's virus).

The high-quality, malignant and not specified new growths (including cysts and polyps): often – a miyelodisplastichesky syndrome and an acute myeloleukemia (mainly, connected with the previous, accompanying or subsequent treatment by the alkylating drugs, inhibitors of topoisomerase or radiation therapy); infrequently – a syndrome of a lysis of a tumor.

The general frustration and disturbances in an injection site: very often – fervescence, increased fatigue, weakness; often – a fever, an indisposition, hypostases.

Interaction with other medicines:

• With pentostatiny. Use of a fludarabin in a combination with pentostatiny (dezoksikoformitsiny) for treatment of HLL often led to a lethal outcome because of high pulmonary toxicity. Therefore it is not recommended to appoint флударабин in a combination with pentostatiny.
• With Dipiridamolum. Dipiridamolum or other inhibitors of the return capture of adenosine can reduce a therapeutic effectiveness of a fludarabin.
• With Cytarabinum. At use of a combination of a fludarabin and Cytarabinum for patients with HLL pharmacokinetic interaction was observed. Clinical trials and the researches in vitro showed that use of a fludarabin in a combination with Cytarabinum can increase concentration ara-TsTF (an active metabolite of Cytarabinum) in leukemic cells. Concentration of Cytarabinum in a blood plasma and the speed of its removal at the same time did not change.

Contraindications:

• Renal failures with clearance of creatinine <30 ml/min.
• Dekompensirovanny hemolitic anemia.
• Pregnancy and period of breastfeeding.
• Hypersensitivity to a fludarabin and/or other components of drug.
• Children's age (efficiency and safety of use of a fludarabin for children are not established).

With care. Флидарин® it has to be appointed with care after careful assessment of a ratio risk/advantage to the weakened patients, especially with heavy dysfunctions of marrow (thrombocytopenia, anemia and/or a granulocytopenia), with a renal failure (clearance of creatinine of 30-70 ml/min.), with a liver failure, an immunodeficiency, opportunistic infections in the anamnesis, to patients    75 years are more senior.

Also with care of Flidarin® it is necessary to appoint at a lactose intolerance, deficit of lactase, a syndrome of glyukozo-galaktozny malabsorption (since drug contains lactose).

Overdose:

At use in the doses exceeding recommended флударабин causes development of a leukoencephalopathy, acute toxic leukoencephalopathy or syndrome of a reversible back leukoencephalopathy. Symptoms can include a headache, nausea, vomiting, spasms, vision disorders (such as sight loss), disturbance of sensitivity and focal neurologic symptomatology, and also an optic neuritis and a papillitis, confusion of consciousness, drowsiness, agitation, a paraparesis / квадропарез, the spasticity and an incontience, irreversible changes in the central nervous system including a blindness, a coma and death. Use of a fludarabin in the doses exceeding recommended is also connected with development development of heavy thrombocytopenia and a neutropenia owing to suppression of function of marrow. In case of the menacing symptoms drug should be cancelled and carried out immediately a maintenance therapy. The specific antidote is not known.

Storage conditions:

In the place protected from light at a temperature not above 25 °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:

Tablets, film coated 10 mg. On 10 tablets in a blister strip packaging, on 1 or 2 blister strip packagings together with the application instruction place in a cardboard pack.