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  • Methotrexat “Ebewe”
    / Novartis


    Active Ingredient
    Methotrexate 2.5 mg, 100 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Vial

    5 ml X 100 mg/ml

    partial basket chart 58780 13555

    Tablets

    50 X 2.5 mg

    partial basket chart 58781 13510

    Related information


    Dosage

    Malignant tumors & hemoblastoses: In polychemotherapy of malignant tumors & hemoblastoses the dosage of methotrexate has to be adjusted according to the indication, general condition & the blood counts of the patient. The administered dose in conventional low-dose MTX therapy (single dose lower than 100 mg/m²), medium-dose MTX therapy (single dose 100 mg/m² – 1000 mg/m²) and high-dose MTX therapy (single dose higher than 1000 mg/m²) depends on the respective therapy protocol.
    The following dosage instructions are only guidelines:
    Conventional dose of methotrexate therapy – no calcium folinate rescue required: 15–20 mg/m² IV – twice weekly; 30–50 mg/m² IV – once weekly; 15 mg/m² day IV/IM – given at 2–3 weeks intervals.
    Intermediate dose of methotrexate therapy: 50–150 mg/m² IV injection- no calcium folinate rescue required, given at 2–3 weeks intervals; 240 mg/m² IV infusion over 24 h; calcium folinate rescue required, given at 4–7 days intervals 500–1000 mg/m², IV infusion over 36–42 h; calcium folinate rescue required given at 2–3 weeks intervals.
    High-dose methotrexate therapy:  calcium folinate rescue required 1–12 gm/m² IV over 1–6 hours, given at 1–3 weeks intervals.
    For intrathecal or intraventricular methotrexate therapy a maximum dose of 15 mg/m² is administered.
    Intrathecal route of administration: 0.2–0.5 mg/kg or 8–12 mg/m² methotrexate is administered every 2–3 days, after disappearance of the symptoms at weekly intervals & subsequently at monthly intervals until CSF findings return to normal. Prophylactic intrathecal instillation should be carried out every 6–8 weeks.
    In severe, generalized, therapy-resistant psoriasis vulgaris including

    psoriatic arthritis and other autoimmunopathies: It is recommended that a test dose of 5-10 mg may be parenterally administered one week prior to initiation of therapy, in order to detect idiosyncratic adverse effects. The recommended initial dose is 7.5 mg methotrexate once weekly. The dose should be increased as necessary but should not exceed a maximum weekly dose of 25 mg of methotrexate.
    Dosage should be adjusted according to the general condition of the
    patient.
    Response to treatment can be expected after approximately 2-6 weeks.
    Once the desired therapeutic result has been achieved, dosage should be
    reduced gradually to the lowest possible effective maintenance dose.
    In therapy-resistant rheumatoid arthritis: Generally 7.5–15 mg methotrexate administered IM/SC initially, as a massive-dose therapy once weekly. Dosage can be increased by 2.5 mg weekly, to a maximum of 25 mg weekly.
    Response to treatment can be expected after approximately 4-8 weeks.
    Once the desired therapeutic result has been achieved, dosage should be
    reduced gradually to the lowest possible effective maintenance dose.
    In patients with impaired renal function the therapy risk should be
    carefully considered and the dosage should be reduced correspondingly
    if required.
    Method of Administration: Methotrexat “EBEWE” Pre-filled Syringe: Should be given IV, IM or SC. Use only clear and freshly prepared solutions.


    Indications

    Antineoplastic chemotherapy: treatment of gestational choriocarcinoma, chorioadenoma destruents and hydatidiform mole. Palliation of acute lymphocytic leukemia. In the treatment and prophylaxis of meningeal leukemia. Greatest effect has been observed in palliation of acute lymphoblastic (stem cell) leukemias in children. In combination with other anticancer agents, Methotrexate may be used for the induction of remission, but is most commonly used in maintenance of induced remissions. Abitrexate may be used alone or in combination with other antineoplastics in the management of breast cancer, epidermoid cancers of the head and neck, lung cancer (particularly squamous cell and small cell types), bladder cancer and osteogenic cancer. Methotrexate is effective in the treatment of the advanced stages (III and IV Peter’s Staging System) of lymphosarcoma, particularly in children, and in advanced cases of mycosis fungoides.
    Psoriasis: Methotrexate is indicated only in the symptomatic control of severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, and only when the diagnosis has been established, as by biopsy and/or after dermatological consultation.
    Rheumatoid Arthritis: Methotrexate can be used in the treatment of selected adults with severe rheumatoid arthritis, only when the diagnosis has been well established according to rheumatological standards, with inadequate response to other forms of antirheumatic therapy, including full dose NSAIDs and usually a trial of at least one or more disease-modifying antirheumatic drugs.


    Contra-Indications

    • Known hypersensitivity to any component of the drug
    • Severe hepatic and renal impairment (serum creatinine > 2 mg%: contraindication; serum creatinine 1.5–2 mg%: dose to be reduced to
    25% of the stated dose)
    • Alcoholism
    • Diseases of the hematopoietic system (bone marrow hypoplasia,
    leucopenia, thrombocytopenia, anemia)
    • Existing infections
    • Ulcers of the oral cavity and gastrointestinal tract
    • Fresh surgical wounds
    • Pregnancy and lactation (use of reliable method of contraception is
    mandatory before, during and after methotrexate therapy both in men
    and women.)
    Particular care should be taken in impairment of bone marrow after an intensive radiotherapy, chemotherapy and/or prolonged pretreatment with drugs impairing bone marrow (sulphonamides, chloramphenicol, pyrazole derivatives, indomethacin, diphenylhydantoin); patients with poor general health, children and the elderly.
    Methotrexate should not be used for the treatment of rheumatoid arthritis or psoriasis vulgaris in patients with pre-existing severe lung disease.
    Caution should be exercised in patients with third space fluid collections (ascites, pleural effusion, seroma at site of operative wounds), since excretion
    of methotrexate may be reduced resulting in increase of toxicity.


    Special Precautions

    Methotrexate should be administered only under the supervision of a qualified physician experienced in the use of antineoplastic therapy.
    Special care should be taken when methotrexate is co-administered with non-steroidal anti-inflammatory drugs (NSAIDs). Severe side effects including fatalities (after high doses of methotrexate) have been reported.
    Consumption of alcohol even in low doses should be avoided.
    The patient should be informed about possible risks (side effects).
    Contraindications and precautions for use must be strictly observed because of possible severe (under particular circumstances lethal) toxic reactions.
    Plasma concentration of methotrexate
    • Higher than 1–2 times 10^-5 mol/l (24 hours after initiating methotrexate therapy)
    • Twice 10^-6 mol/l (48 hours after initiating methotrexate therapy)
    • 10^-7 mol/l (72 hours after initiating methotrexate therapy)
    indicate an increased risk of intoxication (myelosuppression, mucositis) and require a long-lasting and high dose of calcium folinate rescue therapy.
    In patients with impaired renal functions methotrexate dosage has to be reduced accordingly.
    In the case of high dose of methotrexate the creatinine clearance should be at least 75% of the normal value (50 ml/min/m² resp. 90 ml/min).
    An intermediate dose of methotrexate (> 100 mg/m²) should not be prescribed if the creatinine clearance is reduced below 50% of the normal value (< 35 ml/min/m² resp. < 60 ml/min), unless daily determination of serum creatinine, methotrexate levels and calcium folinate rescue performed till the methotrexate levels decrease below 10^-7 mol/l.
    During the conventional dose of methotrexate a dose reduction of 50% is recommended if the serum creatinine values are 1.2–2 mg/dl and cessation of therapy is recommended if serum creatinine values exceed 2 mg/dl.
    Prerequisites for a medium or high-dose methotrexate administration:
    • Adequate availability of calcium folinate for subsequent rescue therapy
    • Rapid determination of methotrexate serum levels
    • Availability of hemodialysis
    • Autologous bone marrow or blood supplies, leukocytes and platelet concentrates
    Pretreatment examinations and safety precautions:
    • Exclusion of renal and liver impairment and disturbances of the hemopoietic system (renal and liver function tests, complete blood counts).
    • Before treatment of rheumatoid arthritis with methotrexate in patients with hepatic disease a liver biopsy should be performed.
    • Pregnancy should be excluded.
    For prevention of intrarenal precipitation of methotrexate or its metabolites and for prophylaxis and treatment of hyperuricemia resulting from destruction of the cell nucleus, forced hydration and alkalization of the urine (by infusion of NaHCO3 solution, 20–25 mmol/l in an amount of 3 l/m²/24 hours) 24 hours before and up to 24 hours after methotrexate administration is required.
    If necessary 150–220 mg/m²/day acetazolamide or allopurinol: 8 mg/kg/day can be used.
    An intermediate and high-dose methotrexate therapy should not be initiated when urinary pH values are below 7.0. The alkaline status of the urine must be controlled at least during the first 24 h after initiation of methotrexate administration (pH value ≥ 6.8).
    Monitoring of methotrexate serum levels is mandatory immediately after cessation of methotrexate administration, as well as 24 h, 48 h and 72 h afterwards. On the basis of methotrexate serum levels, the occurrence of signs of toxicity can be inferred and the calcium folinate dosage can be adjusted.
    During the intrathecal administration systemic side effects may occur.
    A careful clinical examination of the patients, particularly inspection of the oral cavity, pharynx and larynx for changes in mucosa, regular monitoring of leucocytes and thrombocytes (daily up to 3 times weekly), complete blood count (once weekly), renal and liver functions should be performed.
    During long-term or high-dosage therapy, bone marrow biopsies may be necessary.
    In severe leucopenia the risk of an infection should be borne in mind. In case of infection, therapy should be stopped and appropriate antibiotic therapy should be instituted. In severe cases of myelosuppression the transfusion of blood, leucocytes and thrombocytes may be necessary.


    Side Effects

    Many side effects of methotrexate therapy are unavoidable being due to the pharmacological actions of the drug. However, these adverse effects are generally reversible if detected early. The major toxic effects of methotrexate occur in normal, rapidly proliferating tissues, particularly bone marrow and the gastrointestinal tract. Ulcerations of the oral mucosa are usually the earliest signs of toxicity. The most commonly reported adverse effects are difficulty in swallowing, ulcerative stomatitis, pharyngitis, leucopenia, thrombocytopenia, nausea, vomiting and abdominal distress; however, as for other cytotoxic drugs, different toxicities may occur with different frequency/intensity according to different doses/routes of administration.
    Other reported adverse effects include malaise, undue fatigue, chills and fever, dizziness, decreased resistance to infection, tinnitus, blurred vision and eye discomfort. The incidence and severity of side effects appear to be dose-related.
    See prescribing information for full details.


    Drug interactions

    Several drugs may cause interactions (mainly pharmacokinetic) during concomitant administration of methotrexate.
    The activity of methotrexate is increased by:
    Inhibition of the renal excretion of methotrexate with non-steroidal antiinflammatory drugs, salicylates, sulphonamides, probenecid, cephalothin,
    penicillin, carbenicillin, ticarcillin, para-aminohippuric acid.
    Drugs which are involved in the active tubular secretion impair the elimination of methotrexate and therefore cause an increased plasma concentration.
    The displacement of the methotrexate which is bound to plasma proteins leads to a higher free concentration in the plasma, e.g. with salicylates, sulfisoxazole, sulfafurazole, doxorubicin, bleomycin, cyclophosphamide, phenytoin, barbiturates, tranquilizers, tetracyclines, chloramphenicol, p-aminobenzoic acid, oral antidiabetics (chlorpropamide, amidopyrine derivatives), diuretics.
    Increase of the intracellular accumulation of methotrexate and methotrexate polyglutamates, e.g. with vinca alkaloids, epipodophyllotoxins, probenecid.
    The activity of methotrexate is decreased by:
    Inhibition of the intracellular uptake of methotrexate (corticosteroids, L-asparaginase, bleomycin, penicillin); increase of the dihydrofolate reductase concentration (triamterene) or increase of the intracellular purine concentration (allopurinol); vitamin preparations which contain folic acid or its derivatives (especially folinic acid).
    Drugs with known hepatotoxicity should not be administered concomitantly with methotrexate due to increased risk of hepatoxicity.
    Drugs with folic acid antagonist activity (pyrimethamine, trimethoprim) may increase the toxicity of methotrexate.
    The myelosuppressive activity can increase due to long-lasting pretreatment with myelosuppressive substances (e.g. sulphonamide, chloramphenicol, pyrazole derivatives, indomethacin, and diphenylhydantoin).
    Methotrexate can enhance the activity of coumarin-like oral anticoagulants (the prothrombin time is prolonged due to a reduced decomposition of coumarin derivatives).
    During simultaneous parenteral administration of acyclovir and intrathecal administration of methotrexate, neurological disorders can not be excluded.
    Methotrexate may impair the immunologic reaction to vaccinations and may lead to severe complications. Therefore vaccinations should not be carried out during methotrexate therapy.
    According to the type and intensity of the myelosuppressive therapy of the disease and other factors the ability to respond normally to vaccination may take 3–12 months. Leukemia patients in remission should not be vaccinated with live vaccines at least 3 months after the last dose of methotrexate.
    The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate metabolism, yielding severe unpredictable myelosuppression and stomatitis. This effect can be reduced by the use of folinic acid rescue.
    Amiodarone administration to patients receiving methotrexate treatment for psoriasis has induced ulcerated skin lesions.
    An increased risk of hepatotoxicity has been reported when methotrexate and etretinate are given concurrently.


    Pregnancy and Lactation

    Methotrexate is a teratogenic drug; abortion, fetal death and/or congenital
    abnormalities have been reported. Therefore, it is not recommended in
    women of childbearing potential unless the potential benefits can be
    expected to outweigh the risks. If the drug is used during pregnancy
    for antineoplastic indications, or if the patient becomes pregnant while
    taking this drug, the patient should be informed on the potential hazard
    to the fetus.
    For the management of psoriasis or rheumatoid arthritis, methotrexate
    therapy in women should be started immediately following a menstrual
    period.
    Appropriate measures should be taken in men or women to avoid
    conception during and for at least 6 months following cessation of
    methotrexate therapy.


    Overdose

    Calcium folinate is the antidote for neutralizing the immediate toxic effects of methotrexate on the hematopoietic system.
    When large doses or overdoses are given, calcium folinate may be administered by intravenous infusion in doses up to 75 mg within 12 hours, followed by 12 mg intramuscularly every 6 hours for 4 doses. When average doses of methotrexate appear to have an adverse effect, 6–12 mg of calcium folinate may be given intramuscularly every 6 hours for 4 doses.
    In general, where overdosage is suspected, the dose of calcium folinate should be equal to or higher than the offending dose of methotrexate and should be administered as soon as possible; preferably within the first hour and certainly within 4 hours after which it may not be effective.
    Other supporting therapy such as blood transfusion and renal dialysis may be required.
    Effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyser.


    Important notes

    Shelf Life: 2 years.
    Storage: Store in the original package in order to protect from light. Do not store above 25°C. Do not freeze.


    Manufacturer
    Ebewe Pharma
    Licence holder
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