Active substanceFludarabineFludarabine
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  • Dosage form: & nbspfilm-coated tablets
    Composition:

    1 tablet, film-coated, contains:

    active substance: fludarabine phosphate 10.0 mg;

    Excipients: lactose monohydrate 110.25 mg, pregelatinized starch 20.0 mg, crospovidone 4.5 mg, sodium stearyl fumarate 4.5 mg, silicon dioxide colloid 0.75 mg;

    shell: film coating 4.0 mg (iron oxide red oxide (E 172) (0.68%), talc (30.77%), iron dye oxide yellow (E 172) (0.68%), hypromellose (38.46 %), titanium dioxide (E 171) (29.41%).

    Description:

    Tablets are capsular-shaped, biconvex, covered with a film membrane from orange-pink to pink, with an engraving "10" on one side. On the transverse section, the tablets are white.

    Pharmacotherapeutic group:antitumour agent - antimetabolite
    ATX: & nbsp

    L.01.B.B.05   Fludarabine

    Pharmacodynamics:

    Flugarda® contains fludarabine phosphate, a fluorinated nucleotide analogue of the antiviral agent vidarabine, 9-β-D-arabinofuranosyladenine (ara-A), which is relatively resistant to deamination by adenosine deaminase. In humans, fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A, which, captured by cells, is then intracellularly phosphorylated to the active triphosphate (2-fluoro-ara-ATP). This metabolite inhibits RNA reductase, DNA polymerase (alpha, delta, and ipsylon), DNA primase, and DNA ligase, which leads to a disruption in DNA synthesis. In addition, RNA polymerase II is partially inhibited, followed by a decrease in protein synthesis. Research in vitro showed that the effect of 2-fluoro-ara-A on the lymphocytes of patients with chronic lymphocytic leukemia (CLL) activates the mechanism of intensive DNA fragmentation and apoptosis.

    Toxic. Has teratogenic activity. Mutagenic properties do not.

    Pharmacokinetics:

    He there was a clear correlation between the pharmacokinetics of fludarabine and its therapeutic effect in cancer patients, with the frequency of detection of neutropenia and changes in hematocrit-dose-dependent.

    Fludarabine phosphate (2-fluoro-ara-AMP) is a water soluble precursor of fludarabine (2-fluoro-ara-A), in the human body, 2-fluoro-ara-AMP is rapidly and completely dephosphorylated to the nucleoside of 2-fluoro-ara-A. Linkage to blood plasma proteins is insignificant.

    2-Fluoro-ara-A is actively transported to leukemic cells, after which it is rephosphorylated to monophosphate and partially to di- and triphosphate. Triphosphate (2-fluoro-ara-ATP) is the main intracellular metabolite and the only known metabolite with cytotoxic activity. The concentration of 2-fluoro-ara-ATP in leukemic rivets was also significantly higher than its maximum concentration in the plasma, indicating a cumulation of the substance in the tumor cells. The half-life of 2-fluoro-ara-ATP from the target cells averages from 15 to 23 hours.After oral administration, the maximum concentration (CmOh) (20-30% of the concentration determined by the end of intravenous infusion) in the blood is observed after 1-2 hours. Bioavailability is 50-65%.

    Food slightly (less than 10%) increases the area under the curve and reduces TmOh (time to reach the maximum concentration) and CmOh, does not change the half-life.

    With chronic renal failure, its clearance is reduced.

    Indications:

    - B-cell chronic lymphocytic leukemia (CLL);

    - Non-Hodgkin's low-grade lymphomas (NHL NHS);

    - follicular B-cell lymphomas;

    - lymphoma from the cells of the mantle zone.

    Contraindications:

    - Hypersensitivity to fludarabine or other components of the drug;

    - impaired renal function with creatinine clearance <30 mL / min;

    - decompensated hemolytic anemia;

    - pregnancy and the period of breastfeeding;

    - children's age (lack of sufficient clinical data).

    Carefully:

    Fluguarda® should be used with caution after a thorough assessment of the risk / benefit ratio for patients in a weakened state, patients with a marked decrease in bone marrow function (thrombocytopenia, anemia,and / or granulocytopenia), immunodeficiency or with opportunistic infections in the history, patients older than 75 years, patients with renal insufficiency (creatinine clearance - 30-70 ml / min), patients with hepatic insufficiency, a patient with lactase deficiency, lactose intolerance, glucose syndrome -galactose malabsorption.

    Pregnancy and lactation:

    Use in pregnant women and during lactation is contraindicated.

    Also, pregnant women are prohibited from working with the drug.

    Dosing and Administration:

    The recommended dose for ingestion is 40 mg / m2 the body surface daily for 5 days every 28 days. The table provides recommendations for determining the number of tablets for admission, depending on the body surface area (PPT):

    The recommended number of tablets depending on the patient's body surface area

    PPT

    Total dose 40 mg / m2

    Number of tablets, mg

    0,75-0,88

    30-35 mg

    3 (30 mg)

    0,89-1,13

    36-45 mg

    4 (40 mg)

    1,14-1,38

    46-55 mg

    5 (50 mg)

    1,39-1,63

    56-65 mg

    6 (60 mg)

    1,64-1,88

    66-75 mg

    7 (70 mg)

    1,89-2,13

    76-85 mg

    8 (80 mg)

    2,14-2,38

    86-95 mg

    9 (90 mg)

    2,39-2,50

    96-100 mg

    10 (100 mg)

    Tablets can be taken either on an empty stomach or simultaneously with a meal. Tablets should be swallowed whole (do not chew, do not break), washing down with water.The duration of treatment depends on the effect and tolerability of the drug. Flugard® should be used until the maximum response is achieved (complete or partial remission, usually 6 cycles), after which treatment should be discontinued.

    Correction of the dosing regimen

    Patients with impaired renal function

    In case of creatinine clearance from 30 to 70 ml / min, the dose should be reduced by 50%. When carrying out therapy in such patients, permanent hematologic control is necessary.

    Patients with impaired hepatic function

    The safety and efficacy of fludarabine have not been studied in patients with impaired hepatic function. Care should be taken in this category of patients.

    Hematological toxicity

    If at the beginning of the subsequent cycle there is a marked decrease in the absolute number of neutrophils and / or platelets, the planned treatment cycle should be postponed until the number of neutrophils reaches 1.0x109/ l, and thrombocytes - 100x109/ l and higher. Treatment can be delayed for a maximum of two weeks. If the absolute number of neutrophils and platelets has not reached these values ​​after the expiration of the two pedules, treatment should be continued using a reduced dose in accordance with the table below.

    Absolute number of neutrophils

    (109/ l )

    Platelet count

    (109/ l )

    Dose of the drug

    0,5-1,0

    50-100

    30 mg / m2/day

    <0,5

    <50

    20 mg / m2/day

    If thrombocytopenia is associated with a major disease, dosage adjustment is not required.

    Use in special patient groups

    Children

    Efficacy and safety in children not studied

    Elderly patients

    Since there are limited data on the use of fludarabine in elderly patients (over 75 years of age), the drug should be used with caution in this category of patients.

    Side effects:

    The incidence of adverse events is indicated on the basis of clinical trial data, regardless of the cause-and-effect relationship with fludarabine, according to the following gradation: very often (≥10%), often (<10% -≥1%), infrequently (<1% - ≥0,1%), rarely (<0,1% - ≥0,01%), the frequency is unknown.

    Infectious and parasitic diseases

    Very often - joining of secondary infections / opportunistic infections (for example, reactivation of latent viruses, including herpes and Epstein-Barr viruses, progressive multifocal leukoencephalopathy), pneumonia;

    rarely - lymphoproliferative disorders (associated with the Epstein-Barr virus).

    Violations of the blood and lymphatic system

    Very often - neutropenia, thrombocytopenia and anemia;

    often - myelosuppression.

    Immune system disorders

    Infrequently, autoimmune disorders (including autoimmune hemolytic anemia, thrombocytopenic purpura, pemphigus, Evans syndrome, acquired hemophilia).

    Disorders from the gastrointestinal tract

    Very often - nausea, vomiting, diarrhea; often - anorexia, stomatitis, mucositis;

    infrequently - gastrointestinal bleeding, changes in the activity of liver and pancreatic enzymes.

    Disorders from the metabolism and nutrition

    Infrequently - as a result of tumor lysis, hyperuricemia, hyperphosphataemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria and renal insufficiency may develop.

    Disturbances from the nervous system

    Often - peripheral neuropathy;

    infrequently - confusion of consciousness; rarely excitation, convulsions, coma.

    Disturbances on the part of the organ of sight

    The privateo - impaired vision;

    rarely - optic neuritis, optic nerve neuropathy and blindness.

    Disturbances from the respiratory system, chest and mediastinal organs

    Very often - cough;

    infrequently - shortness of breath, pulmonary fibrosis, pneumonitis.

    Heart Disease

    Rarely - heart failure, arrhythmias.

    Disorders from the kidneys and urinary tract

    Rarely, hemorrhagic cystitis.

    Disturbances from the skin and subcutaneous tissues

    Often - skin rash;

    Rarely, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome). There have been reports of rare cases of increased growth of skin cancer, as well as the development of skin cancer during or after treatment with fludarabine.

    General disorders and disorders at the site of administration

    Very often - fever temperature increase, fatigue, weakness;

    Often - chills, malaise, swelling.

    Benign, malignant and unspecified neoplasms (including cysts and polyps)

    In patients who received fludarabine before, after or simultaneously with alkylating antistatic agents, topoisomerase inhibitors or radiotherapy, in rare cases, myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML) was observed.

    Post-registration data

    Disturbances from the nervous system

    The frequency is unknown - leukoencephalopathy, acute toxic leukoencephalopathy, reversible leukoencephalopathy syndrome (COPD).

    Vascular disorders

    The frequency is unknown - bleeding (including cerebral bleeding, pulmonary hemorrhage).

    Overdose:

    High doses of fludarabine cause irreversible changes in the central nervous system, including blindness, coma and death. Application of fludarabine in doses 4 times higher than recommended (95 mg / m2/ day for 5-7 days), neurotoxicity was observed in approximately 36% of patients, with neurotoxicity symptoms appearing 21-60 days after the last dose.

    Use in doses exceeding the recommended, is also associated with the development of severe thrombocytopenia and neutropenia due to the suppression of bone marrow function.

    Specific antidotes with an overdose of fludarabine are unknown. Treatment consists in stopping the administration of the drug and conducting maintenance therapy.

    Interaction:

    The use of fludarabine in combination with pentostatin (desoxicoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL) has often resulted in death due to high pulmonary toxicity, therefore the use of Flugard® in combination with pentostatin is not recommended.

    Dipyridamole or other inhibitors of adenosine reuptake may decrease the therapeutic efficacy of fludarabine.

    In the treatment with a combination of fludarabine and cytarabine in patients with chronic lymphatic leukemia and acute myeloid leukemia, a pharmacokinetic interaction was observed. When co-administration of cytarabine with fludarabine is combined, higher intracellular peak concentrations and intracellular AUC metabolite of cytarabine - arabinosyl cytosine triphosphate. Plasma concentrations of cytarabine and excretion of arabinosyl cytosine triphosphate remained unchanged.

    Special instructions:

    Treatment with Flugard® should be performed under the supervision of a physician experienced in the use of cytotoxic agents.

    When Flugard® is used, periodic peripheral blood tests are recommended to assess anemia, neutropenia and thrombocytopenia, carefully monitor serum creatinine and creatinine clearance, and monitor closely the CNS function, in order to identify possible neurological disorders in a timely manner.

    Oppression of the bone marrow is usually reversible.In fludarabine therapy of solid tumors in adults, the greatest decrease in the number of neutrophils is observed on average 13 days (3-25 days) from the start of treatment, platelets - on average for 16 days (2-23 days). Myelosuppression can be expressed and have a cumulative character. Several cases of bone marrow hypoplasia or aplasia in adults with pancytopenia, sometimes fatal, have been described. The duration of clinically significant pancytopenia ranged from 2 months to 1 year. These episodes were detected in both treated and untreated patients. Effects of prolonged use of fludarabine on the central nervous system are unknown. When Flugard® is used, it is recommended that the central nervous system be monitored, in connection with the possible neurotoxicity of the drug, which is described in fludarabine therapy in high doses. As part of the postgraduate experience with fludarabine, there have been cases of leukoencephalopathy, acute toxic leukoencephalopathy, and reversible leukoencephalopathy syndrome. However, in some studies it has been shown that with a relatively long-term use (up to 26 courses of therapy), fludarabine is satisfactorily tolerated by patients.

    On the background of fludarabine therapy, development of serious opportunistic infections, in some cases leading to death, was noted. Patients with an increased risk of developing opportunistic infections are recommended to conduct preventive therapy.

    Regardless of the absence of autoimmune processes in the anamnesis, as well as the results of the Coombs test, the occurrence of life-threatening and sometimes fatal autoimmune reactions (autoimmune hemolytic anemia, autoimmune thrombocytopenia, thrombocytopenic purpura, pemphigus, Evans syndrome) during or after treatment with fludarabine . Most patients with hemolytic anemia experienced recurrence of hemolysis after a provocative test with fludarabine.

    Free, receiving treatment with fludarabine, should be carefully observed for signs of hemolytic anemia. In the case of hemolysis, discontinuation of fludarabine therapy is recommended. The most common therapeutic measures for hemolytic anemia are transfusion of irradiated blood and glucocorticosteroid therapy.

    In rare cases, patients who received fludarabine before, after or simultaneously with alkylating cytostatic agents, topoisomerase inhibitors or radiotherapy, observed myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML). When fludarabine monotherapy with MDS / AML was not observed. The "graft versus host" reaction (the reaction of transfused immunocompetent host ligocytes) resulting from hemo transfusions was observed after transfusion of unirradiated blood to patients treated with fludarabine. A high incidence of fatalities has been reported as a consequence of this disease. In this regard, patients who need hemo transfusions and who receive or received treatment with fludarabine, only irradiated blood should be transfused.

    Single cases of skin cancer have been reported, as well as an increase in the growth of skin cancer already present, during or after treatment with fludarabine.

    Since Flugard® can cause tumor lysis as early as the first week of therapy, caution should be exercised in treating patients at risk of developing this syndrome (especially with a large tumor mass).

    Due to the lack of clinical data on the use of fludarabine in elderly patients (over 75 years), fludarabine at this age should be applied with caution.

    It should be borne in mind that patients resistant to fludarabine therapy in most cases show resistance to chlorambucil.

    Fertile women and men should use case-based contraceptive methods during treatment and at least 6 months after the end of therapy.

    During and after treatment with fludarabine, vaccination with live vaccines should be avoided.

    Precautions for use

    When handling fludarabine, the weight of the instructions taken to use and destroy cytotoxic drugs should be observed. Avoid inhalation of the drug. It is recommended to use protective glasses and latex gloves. In case of contact with the skin or the mucous membranes of the leg, the areas should be thoroughly rinsed with water and soap. In case of contact with eyes, rinse thoroughly with plenty of water.

    Pregnant women are not allowed to work with fludarabine.

    Effect on the ability to drive transp. cf. and fur:

    Some side effects of the drug, such as increased fatigue, weakness, visual impairment, can adversely affect the ability to drive and perform potentially dangerous activities requiring increased concentration and speed of psychomotor reactions. When these undesirable phenomena appear, one should refrain from performing these activities.

    Form release / dosage:

    Tablets coated with a film coating, 10.0 mg.

    Packaging:

    5 tablets per contour cell package.

    By 2, 3, 4 or 5 contour mesh packages together with instructions for use in a pack of cardboard.

    Storage conditions:

    Keep in dry the dark place at a temperature of no higher than 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002865
    Date of registration:19.02.2015
    Date of cancellation:2020-02-19
    The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia
    Manufacturer: & nbsp
    Representation: & nbspBIOCAD CJSC BIOCAD CJSC Russia
    Information update date: & nbsp26.09.2015
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