Clinical and pharmacological group: & nbsp

Antimetabolites

Included in the formulation
  • Vero-Fludarabine
    lyophilizate in / in 
    VEROPHARM SA     Russia
  • Darbines
    pills inwards 
  • Flugard®
    pills inwards 
    BIOCAD, CJSC     Russia
  • Flugard®
    lyophilizate in / in 
    BIOCAD, CJSC     Russia
  • Fludara®
    lyophilizate in / in 
    Genzyme Europe BV     Netherlands
  • Fludara®
    pills inwards 
    Genzyme Europe BV     Netherlands
  • Fludarabel®
    pills inwards 
    FARMSINTEZ, PAO     Russia
  • Fludarabine
    lyophilizate in / in 
    BELMEDPREPARATY, RUP     Republic of Belarus
  • Fludarabin-Aktavis
    lyophilizate in / in 
  • Fludarabine-Teva
    concentrate in / in 
  • Fludarabine-TL
    pills inwards 
  • Fludarabine-Ebwe
    concentrate in / in 
  • Flutoter®
    pills inwards 
  • Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

    VED

    АТХ:

    L.01.B.B.05   Fludarabine

    Pharmacodynamics:

    Antitumor drug. Contains fludarabine phosphate, a fluorinated nucleotide analogue of an antiviral agent, a species of rabbit, 9-β-D-arabinofuranosyladenine (ara-A), which is relatively resistant to deamination by adenosine deaminase.

    In humans, fludarabine phosphate rapidly dephosphorylated to 2-fluoro-arabinofuranosyladenine (2-fluoro-ara-A) which is trapped by the cells, then intracellularly to the active refosforiliruetsya deoxycytidine 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 K is partially inhibited, followed by a decrease in protein synthesis.

    Pharmacokinetics:

    After intravenous administration fludarabine by dephosphorylation rapidly metabolized to 2-fluoro-ara-AMP, which in turn refosforiliruetsya to 2-fluoro-ara-ATP and is found in the leukemic cells of peripheral blood and bone marrow.

    Elimination occurs in 3 phases: I phase with an initial half-life of 5 minutes; II phase with a half-life of 1-2 hours; terminal phase with half-life about 10 hours. 2-Fluoro-ara-AMP is excreted by the kidneys. The half-life, plasma clearance and volume of distribution are dose independent.

    In patients with severe renal dysfunction, fludarabine clearance decreases, which may require dose adjustment.

    Indications:B-cell chronic lymphocytic leukemia (in case of insufficient effectiveness of other alkylating cytotoxic agents), low-grade non-Hodgkin's lymphomaand. Follicular B-cell lymphomas. Lymphomas from the cells of the mantle zone.

    II.C81-C96.C82.9   Follicular non-Hodgkin's lymphoma, unspecified

    II.C81-C96.C83   Diffuse non-Hodgkin's lymphoma

    II.C81-C96.C85   Other and unspecified types of non-Hodgkin's lymphoma

    II.C81-C96.C91.1   Chronic lymphocytic leukemia

    Contraindications:Hypersensitivityrenal impairment (creatinine clearance less than 30 ml / min), decompensatedhemolytic anemia, pregnancy and lactation, children's age (lack of sufficient clinical data).
    Carefully:

    Efficiency and safety have not been studied.

    Do not recommend applying fludarabine in patients with chicken pox (including recently transferred or after contact with the sick), with herpes zoster, other acute infectious diseases.

    Be wary appoint patients with gout, nephrolithiasis (including in history), with renal insufficiency (creatinine clearance 30-70 ml / min), with hepatic insufficiency, patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

    Apply the drug after a thorough assessment of the risk / benefit ratio for patients in a weakened state, with a marked decrease in bone marrow function (thrombocytopenia, anemia, and / or granulocytopenia), immunodeficiency, acute viral, fungal or bacterial infection, liver failure (efficacy and safety of fludarabine studied), patients older than 75 years.

    Pregnancy and lactation:

    Contraindicated in pregnancy. Action category for the fetus by FDA - D.

    For the duration of treatment, breastfeeding should be discontinued.

    Dosing and Administration:

    Intravenous, infusional, within 30 minutes, bolus slowly. The contents of the vial are dissolved in 2 ml of water for injection. The resulting solution is further diluted with 0.9% sodium chloride solution: for intravenous bolus administration - 10 ml, for intravenous infusion - 100 ml.

    The recommended dose of fludarabine phosphate is 25 mg / m2 body surface daily for 5 days every 28 days with intravenous administration.

    The duration of treatment depends on the effect and tolerability of the drug.

    Patients with chronic lymphatic leukemia fludarabine should be administered until the maximum response is achieved (complete or partial remission, usually 6 cycles), after which the treatment should be discontinued.

    In patients with non-Hodgkin's lymphomas of a low degree of malignancy, treatment with fludarabine is recommended before the maximum response (complete or partial remission) is achieved. After achieving the greatest effect, the need for two consolidation cycles should be discussed. According to clinical trials with non-Hodgkin's lymphomas of low degree of malignancy, the majority of patients received no more than 8 cycles of treatment.

    When treated with the oral form of fludarabine (tablets), the recommended dose is 40 mg / m2 body surface daily for 5 days every 28 days.

    Patients with reduced renal function (with a creatinine clearance of 30-70 ml / min) and those over 70 years of age are reduced by 50%.

    Side effects:

    From the side nervous system and sense organs: fatigue, weakness, anxiety, impaired consciousness and / or vision, peripheral neuropathy; neuritis of the optic nerve, visual neuropathy or blindness.

    From the side cardiovascular system and blood (hematopoiesis, hemostasis): myelosuppression (neutropenia, thrombocytopenia, anemia); heart failure, arrhythmia.

    From the side respiratory system: pulmonary edema or diffuse interstitial pneumonitis with a hypersensitivity reaction (cough, fever, dyspnea).

    From the side organs of the digestive tract: nausea, vomiting, anorexia, diarrhea, gastrointestinal bleeding; stomatitis or inflammation of the oral mucosa.

    From the side metabolism: tumor lysis syndrome (hyperuricemia, hematuria, frequent urination, hyperphosphataemia, hypocalcemia), metabolic acidosis, hyperkalemia, crystalluria, renal insufficiency.

    From the side genitourinary system: hemorrhagic cystitis.

    From the side skin integument: skin rash; Stevens-Johnson syndrome or toxic epidermal necrolysis (Lyell syndrome).

    Other: a decrease in tolerance to infections, edema (edema of the feet and ankles); hair loss.

    Overdose:

    Irreversible central neurotoxicity (central blindness, coma, death), expressed myelosuppression (neutropenia, thrombocytopenia). There is no specific antidote.

    Treatment is symptomatic.

    Interaction:

    Dipyridamole and other inhibitors of adenosine reuptake - it is possible to reduce the therapeutic activity of fludarabine.

    Pentostatin - an increase in the incidence of fatal pulmonary toxicity; combine is not recommended.

    Cytarabine - it is possible to reduce the metabolic activation of fludarabine and increase the intracellular concentration of cytarabine in parallel application.

    The occurrence of severe ototoxicity in the short course of treatment with gentamicin after recent treatment with fludarabine has been described.

    The solution for intravenous administration can not be mixed in one vial with other drugs.

    Special instructions:

    The use of fludarabine should be carried out under the supervision of a qualified physician who has experience of antitumor therapy.

    During the period of treatment, periodic monitoring of the picture of peripheral blood, uric acid level in the blood plasma, laboratory indicators of kidney function is necessary. In the case of hemolysis, therapy is discontinued. Patients at risk of developing tumor lysis syndrome require systematic monitoring of the physician, especially during the first week of treatment.

    In elderly patients, a dose reduction may be required (age-related renal impairment is more likely). Fludarabine caution should be exercised after careful assessment of the risk / benefit ratio for patients in a weakened state, patients with a marked decrease in bone marrow function, immunodeficiency, opportunistic infections, children and patients with hepatic insufficiency (efficacy and safety in children, as well as in patients with hepatic impairment not studied ).

    Patients who receive or receive fludarabine, requiring hemotransfusion, only irradiated blood should be transfused to avoid the "graft versus host" reaction.

    Be wary appoint patients who had previously received cytotoxic drugs or radiation therapy.

    Care must be taken when signs of bone marrow depression appear. Special precautions should be observed in case of thrombocytopenia (rejection of intramuscular injections, urine, feces and secretions for occult blood, refusal to take acetylsalicylic acid, caution when using toothbrushes, threads or toothpicks).Transfusion of platelet mass may be required.

    Care is needed to avoid accidental cuts with sharp objects (including a safety razor, scissors). You should avoid contact sports or other situations in which there may be a hemorrhage or injury.

    Appearance of signs of oppression of bone marrow function, unusual bleeding or hemorrhages, black tarry stools, blood in urine or feces or spot red spots on the skin requires immediate consultation of a doctor. When leukopenia should be carefully monitored for the development of infections. In patients with neutropenia with increasing body temperature, the use of antibiotics must begin empirically.

    To prevent hyperuricemia during treatment, it is important to consume enough fluids and then increase diuresis to ensure the excretion of uric acid, in some cases, the appointment of allopurinol.

    During the period of treatment, vaccination with live viral vaccines is not recommended. Use of live viral vaccines in patients with leukemia in remission should not occur within 3 months after the last course of chemotherapy.Immunization with oral polio vaccine for people in close contact with such a patient, especially family members, should be postponed.

    During treatment with the drug, and also within 6 months after its termination, contraceptives should be used to avoid pregnancy.

    The necessary rules for the use and destruction of the drug should be observed. Dilution of fludarabine should be carried out by trained personnel in a specially equipped place (in special cabinets with extraction), using protective clothing (disposable gloves, goggles, masks), with precautionary measures when preparing injection solutions and destroying needles, syringes, ampoules and unused residue preparation.

    The scattered or remaining product is burned. In case of accidental ingestion of the drug solution on the skin, the affected area should be washed immediately with soap and water, and after contact with eyes, rinse thoroughly with plenty of water. Avoid inhalation of the drug. During pregnancy, nurses are not allowed to work.

    Avoid accidental intravascular drug exposure.

    Impact on the ability to drive vehicles and manage mechanisms.

    Some of the 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.

    Instructions
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