Cytarabine-LENS® (Cytarabin-LANS®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceCytarabineCytarabine
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    • Dosage form: & nbsplyophilizate for solution for injection
    Composition:

    1 bottle contains:

    active substance: cytarabine in terms of dry matter 0.1 g;

    Excipients: povidone low molecular weight (polyvinylpyrrolidone low molecular weight medical) 0,005 g.

    Description:

    The porous mass is white or almost white.

    Pharmacotherapeutic group:antitumour agent - antimetabolite
    ATX: & nbsp

    L.01.B.C.01   Cytarabine

    Pharmacodynamics:

    Cytarabine belongs to the group of antimetabolites of pyrimidine metabolism and is S-phase-specific preparation. It stops the synthesis of DNA in the cell. Antileukemic activity of the drug is obtained as a result of phosphorylation in arabinosyl cytosine triphosphate (Ara-CTF), which competitively inhibits DNA polymerase. In addition, there is evidence that DNA synthesis is also inhibited by the incorporation of cytarabine into DNA and RNA.

    Several mechanisms of development of resistance to cytarabine are known: inhibition of membrane transport, deficiency of phosphorylating enzymes, increased activity of inactivating enzymes, decreased affinity of DNA polymerase or increased pool of deoxy-CTF. Cytotoxic effect is achieved when creating permanent, high intracellular concentrations of Ara-CTF.

    Pharmacokinetics:

    After intravenous administration cytarabine quickly and almost completely turns into an inactive uracil-metabolite Ara-U, under the action of cytidine deaminase in the liver and in other tissues. The half-life in the initial phase is 10 minutes, in the final phase it is about 1-3 hours. Since the activity of deaminase in the central nervous system is minimal, the excretion of cytarabine from the cerebrospinal fluid proceeds slowly, and the half-life of the latter is 2-11 hours. With continuous intravenous infusions of cytarabine in usual doses (100-200 mg / m2 body surface), concentrations of 0.04-0.6 μmol / L are achieved. With subcutaneous administration, the maximum concentration in the plasma is reached within 20-60 minutes. Then a two-phase decrease in concentration occurs.An insignificant part of cytarabine undergoes phosphorylation by kinases at the intracellular level, resulting in the formation of an active metabolite Ara-CTP. The connection with plasma proteins is 15%.

    Cytarabine penetrates the blood-brain barrier. After a continuous infusion into the cerebrospinal fluid, a concentration equal to 10-40% of the plasma concentration is achieved. After the administration of usual or high doses, only 4-10% of the administered dose is excreted by the kidneys unchanged. In the first 24 hours 71-96% of the injected drug is found in urine in the form of Ara-U.

    Indications:

    - Acute non-lymphoblastic and / or lymphoblastic leukemia (for induction of remission, and also as maintenance therapy);

    - prevention and treatment of neuroleukemia (intrathecal administration as a monotherapy, and in combination with other antitumor drugs);

    - treatment of non-Hodgkin's lymphomas;

    - treatment of blast crises in chronic myelogenous leukemia.

    High-dose cytarabine therapy:

    - refractory to therapy non-Hodgkin's lymphomas;

    - refractory to therapy acute non-lymphoblastic and / or lymphoblastic leukemia, as well as variants with unfavorable prognosis;

    - relapses of acute leukemia;

    - secondary leukemia after previous chemotherapy and / or radiation therapy;

    - manifest leukemia after the transformation of the preleukosis;

    - acute non-lymphoblastic leukemia in patients younger than 60 years of age (for consolidation of remission);

    - Blast crises in chronic myelogenous leukemia.

    Contraindications:

    - Hypersensitivity to cytarabine and other components of the drug;

    - Pregnancy and the period of breastfeeding.

    Carefully:

    Hepatic and / or renal failure (due to an increased risk of developing neurotoxicity especially with high-dosage therapy). Drug-induced oppression of hematopoiesis, bone marrow infiltration by tumor cells, acute viral infectious diseases (including chicken pox, shingles), fungal or bacterial nature (risk of serious complications and generalization of the process), diseases in which there is an increased risk development of hyperuricemia (gout or urate nephrolithiasis).

    Pregnancy and lactation:

    The drug is contraindicated for use during pregnancy and during breastfeeding.

    During therapy with cytarabine and at least 6 months after its end, reliable methods of contraception should be used.

    Dosing and Administration:

    The scheme and method of application vary with the use of different chemotherapy regimens.

    Before prescribing the drug is recommended to refer to the special literature.

    Cytarabine can be injected intravenously in droplet or by drop, subcutaneously (usually only used for therapy aimed at maintaining remission), and also intrathecally.

    Average daily dose - 100-200 mg / m2. Elderly patients or with reduced hematopoiesis reserves - 50-70 mg / m2.

    Induction of remission in acute leukemia: in combination with other antitumor drugs - 100 mg / m2/ day as a continuous intravenous infusion, for 7 days or 100 mg / m2 in / in every 12 hours for 7 consecutive days. In total, 4-7 treatment courses are conducted. Intervals between courses - not less than 14 days.

    High-dose therapy: high-dose therapy in the treatment of leukemia with poor prognosis, as well as refractory leukemia and relapses, is performed with cytarabine at a dose of 2-3 g / m2 surface of the body in the form of intravenous infusion lasting 1-3 hours, with a 12-hour interval,for 2-6 days in the form of monotherapy or in combination with other antitumor drugs.

    Intrathecal Therapy: with acute leukemia, the dose of cytarabine is 5-75 mg / m2. The frequency of administration can vary from once a day for 4 days to once in 4 days. Most often cytarabine appoint 30 mg / m2 body surface every 4 days before the normalization of the indicators, followed by another additional introduction. However, the dosage and the intervals between dose administrations depend on the clinical situation.

    In connection with the fact that the dose and mode of administration of Cytarabine depend on specially developed schemes of polychemotherapy in each individual case, one should refer to the special literature.

    With renal and hepatic insufficiency There is no need to reduce the dose of the drug if conventional doses are used. If high-dose therapy is used, the choice of dose should take into account the increased risk of complications from the CNS.

    Preparation of a solution for infusions

    Cytarabine in the required dose is diluted in a 0.9% solution of sodium chloride or in a 5% solution of dextrose.

    The concentration of cytarabine should not exceed 100 mg / ml.

    During perfusion Cytarabine can be used undiluted.

    When intrathecal, lumbar and intraventricular injection of the drug Cytarabine possible to use original solution. It is recommended to first select 5-8 ml of cerebrospinal fluid, mix it with the injection solution in the syringe, and then slowly reverse the introduction of the resulting solution. The use of this route of administration is not associated with a risk of systemic toxic effects.

    Side effects:

    Adverse reactions caused by cytarabine, depend on the dosage, mode of administration and duration of therapy.

    On the part of the hematopoiesis system: leukopenia, thrombocytopenia, anemia, megaloblastosis, reticulocytopenia. The decrease in the number of leukocytes is of a two-phase nature, with the first maximum decrease being achieved by 7-9 days. Then there is a short-term rise with a maximum of 12 days. At the second and deeper decline, the minimum number of leukocytes is observed in 15-24 days. In the next 10 days, the number of white blood cells increases rapidly. The decrease in the number of platelets becomes noticeable by day 5, the minimum occurs between 12-15 days.In the next 10 days there is a rapid increase in the number of platelets to the baseline level. The severity of these reactions depends on the dose and the scheme of administration.

    From the gastrointestinal tract: nausea, vomiting, loss of appetite, abdominal pain, diarrhea, inflammation or ulceration of the gastrointestinal mucosa (oral and rectal cavity, less often - esophagus). Nausea and vomiting most often occur after a rapid intravenous injection. When using high doses (2-3 g / m2) ulceration of the gastrointestinal tract can be severe, it is possible to develop necrotic colitis, small intestine necrosis, cystic pneumatosis of the intestine, leading to peritonitis.

    From the liver and pancreas: a violation of the liver, jaundice. With high-dosage therapy - a violation of liver function with hyperbilirubinemia, sepsis and liver abscess.

    Individual cases of development of thrombosis of hepatic veins (Badd-Chiari syndrome), as well as pancreatitis in the treatment of high doses of cytarabine in combination with other drugs, have also been reported.

    From the nervous system: neuritis, neurotoxicity, headache, dizziness.Disturbances from the central nervous system are mainly observed in high-dose therapy, with disorders of cerebral and cerebellar functions (nystagmus, dysarthria, ataxia, confusion), including personality changes, drowsiness, and coma. Disorders from the CNS are usually reversible. Also reported were cases of peripheral motor and sensory neuropathy and late progressive ascending paralysis. In some cases after the intrathecal administration of the drug, nausea, vomiting, dizziness and fever were noted. These complaints can also be caused by lumbar puncture. Cumulative neurotoxicity may also occur, especially with short intervals between dose administrations. Individual cases of necrotizing leukoencephalopathy, as well as paraplegia and blindness after intrathecal cytarabine injection were described.

    From the side of the musculoskeletal system: when used in high doses, myalgias and / or arthralgias in the neck and lower extremities were observed. A case of rhabdomyolysis is also described.

    From the sense organs: conjunctivitis (photophobia, burning sensation in the eyes, pronounced lachrymation), keratitis. In the treatment of high doses, reversible ulcerative keratitis and hemorrhagic conjunctivitis, visual disturbances may occur.

    From the cardiovascular and respiratory systems: transient arrhythmia, cardiomyopathy (including fatal, when using cytarabine in high doses in combination with cyclophosphamide), pericarditis, sore throat, dyspnea, pneumonia, diffuse interstitial pneumonitis (medium doses - 1 g / m2), progressive respiratory distress syndrome, leading to pulmonary edema and cardiomegaly with possible fatal outcome (high doses of cytarabine).

    From the side of the kidneys and urinary tract: impaired renal function, urinary retention, hyperuricemia, or urate nephropathy.

    From the skin and skin appendages: itching, rash (patchy-papular and urticaria), the appearance of pigment spots on the skin, ulceration of the skin, alopecia. There are rare reports of severe skin rashes leading to desquamation. Local reactions: inflammation of subcutaneous fat at the injection site.

    Infectious complications: viral, bacterial, fungal, parasitic or saprophytic infections of any localization (including sepsis), usually of mild or moderate severity, but can be severe and sometimes fatal (their development is caused by a decrease in immunity).

    Cytarabine Syndrome: fever, muscle pain, bone pain, sometimes pain in the chest, spotty papular rash, conjunctivitis, malaise. These symptoms usually appear 6-12 hours after the administration of the drug.

    It has been established that glucocorticosteroids are effective in treating or preventing the development of this syndrome.

    Other: fever, thrombophlebitis, allergic reactions (including anaphylaxis, urticaria, edema), isolated cases of the syndrome of inadequate production of antidiuretic hormone.

    Overdose:

    Chronic overdose can lead to severe bone marrow depression, which can be accompanied by massive bleeding, the development of life-threatening infections, and the manifestation of neurotoxic action. Since there are no effective antidotes for cytarabine, every injection should be carried out very carefully.If an overdose occurs, then ancillary measures (blood transfusion, antibiotic therapy) should be performed. In case of severe overdose occurring during intrathecal injection, repeated lumbar punctures should be performed to ensure rapid drainage of cerebrospinal fluid, possibly neurosurgical intervention with ventricululumbral perfusion. Cytarabine can be excreted by hemodialysis. However, information on the effectiveness of hemodialysis in case of an overdose of cytarabine is absent.

    Interaction:

    Do not mix in one syringe or dropper with other drugs: pharmaceutically incompatible with heparin, insulin, methotrekeate, 5-fluorouracil, oxacillin, benzylpenicillin, methylprednisolone.

    Co-administration with other antitumor myelosuppressive drugs or radiation therapy increases the cytotoxic as well as immunosuppressive activity of these drugs.

    With the use of polychemotherapy with the inclusion of cytarabine, a reversible decrease in the equilibrium plasma concentration of digoxin was noted (due to a reduction in absorption - a violation of absorption due to toxic effects onintestinal mucosa), as well as a decrease in renal excretion of the glycoside. An alternative for such patients can be considered the use of digitoxin, an equilibrium plasma concentration that does not change.

    Conducted in vitro studies of the interaction between gentamicin and cytarabine revealed the existence of antagonism, which may reduce the sensitivity of strains TO. pneumoniae to gentamicin. It is possible to reduce the effectiveness of fluorocytosine when used simultaneously.

    Immunosuppressants (azathioprine, chlorambucil, glucocorticosteroids, cyclophosphamide, ciclosporin, mercaptopurine, tacrolimus) increase the risk of developing infectious complications.

    Killed virus vaccines - due to the suppression of normal mechanisms, cytarabine can be reduced by the formation of antibodies.

    Live viral vaccines - due to the suppression of normal mechanisms cured with cytarabine, potentiation of viral replication is possible, an increase in side effects, a decrease in the formation of antibodies.

    Special instructions:

    When handling the drug and when using it, the recommendations developed in the safe handling of cytostatics should be followed.

    Induction and consolidation therapy with the use of the drug Cytarabine in acute leukemia should be carried out only in a hospital, under the supervision of experienced oncologists and with careful monitoring. It is necessary to regularly monitor the picture of peripheral blood (daily with induction therapy), the function of the bone marrow, liver and kidneys, as well as the level of uric acid in the serum. With a decrease in platelets below 50,000 or polymorphonuclear granulocytes below 1000 / mm3, it is necessary to suspend or modify therapy. The number of elements in the peripheral blood can continue to fall after the drug is withdrawn and reach a minimum level after 12-24 days. If there are indications, you can resume therapy with clear signs of hematopoiesis recovery from the results of the bone marrow examination.

    When carrying out high-dosage therapy and intrathecal therapy, solutions containing benzyl alcohol should not be used.

    When performing high-dose therapy, continuous monitoring of the central nervous system and lung function should be performed.

    When carrying out high-dosage therapy and impaired liver or kidney function, the likelihood of toxicity from the central nervous system may increase.Patients with impaired liver or kidney function should be administered with caution and, possibly, in a reduced dose.

    Patients receiving high doses of Cytarabine should be monitored for the possibility of developing neuropathy, because to change the occurrence of irreversible neurological disorders, it may be necessary to change the dose or regimen of therapy. When there are symptoms of toxic effects on the central nervous system, a special risk assessment should be carried out; the same actions are necessary and with the appearance of the first symptoms of allergy.

    Like other antitumor drugs Cytarabine can lead to the development of hyperuricemia due to rapid decay of tumor cells. It is recommended to prevent hyperuricemia in patients with high blast cells or with large tumor masses (for example, with non-Hodgkin's lymphomas).

    Vaccination of patients undergoing cytarabine therapy should be carried out very carefully, after careful evaluation of the hematologic status and with the consent of a physician administering cytarabine therapy. The interval between the end of immunosuppressive therapy and vaccination depends on the type of immunosuppressant,the main disease and other factors and varies from 3 months to 1 year.

    Cytarabine is excreted from the body during hemodialysis. Therefore, patients on dialysis should not be administered Cytarabine immediately before and during dialysis.

    Women and men during treatment and within 6 months after treatment should use reliable methods of contraception.

    Do not allow contact with the skin and mucous membranes, especially the eyes.

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

    Data on the effect of cytarabine therapy on the ability to drive a vehicle and work with mechanisms are not available, however, since during drug therapy Cytarabine nausea and vomiting may occur, this can indirectly affect the ability to drive and work with machinery. Therefore, you should carefully consider the action of the drug in the above situations.

    Form release / dosage:

    Liofilizate for the preparation of solution for injection, 100 mg.

    Packaging:

    In vials of 100 mg.

    1 bottle with instructions for use in a pack.

    For 5 or 10 vials of the drug, together with the instruction for use, is placed in a bundle with septums or special nests of cardboard.

    For 35, 50, 85 or 100 vials with instructions for use, at the rate of one instruction for 10 bottles, put in a box of cardboard (for hospitals).

    Storage conditions:

    At a temperature not higher than 8 ° C in a place protected from light and inaccessible to 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:Р N000075 / 01
    Date of registration:20.12.2011
    The owner of the registration certificate:LENS-PHARM, LLC LENS-PHARM, LLC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp27.09.2015
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