Posology : מינונים

Dosage and Administration
• Autologous bone marrow or blood supplies, leukocytes and platelet Dosage concentrates
Malignant tumors and hemoblastoses:
Pretreatment examinations and safety precautions:
In polychemotherapy of malignant tumors and hemoblastoses the dosage
• Exclusion of renal and liver impairment and disturbances of the of methotrexate has to be adjusted according to the indication, general             hemopoietic system (renal and liver function tests, complete blood condition and the blood counts of the patient. The administered dose in             counts).
conventional low-dose MTX therapy (single dose lower than 100 mg/m2), • Before treatment of rheumatoid arthritis with methotrexate in patients medium-dose MTX therapy (single dose 100 mg/m2–1000 mg/m2) and with hepatic disease a liver biopsy should be performed.
high-dose MTX therapy (single dose higher than 1000 mg/m2) depends on the respective therapy protocol.                                               • Pregnancy should be excluded.
The following dosage instructions are only guidelines:                            For prevention of intrarenal precipitation of methotrexate or its metabolites and for prophylaxis and treatment of hyperuricemia resulting from
Conventional dose of methotrexate therapy – no calcium folinate rescue destruction of the cell nucleus, forced hydration and alkalization of the required: urine (by infusion of NaHCO3 solution, 20–25 mmol/l in an amount of 15–20 mg/m2 IV - twice weekly                                                     3 l/m2/24 hours) 24 hours before and up to 24 hours after methotrexate 30–50 mg/m2 IV - once weekly                                                      administration is required.
15 mg/m2/day IV/IM - given at 2–3 weeks intervals                                 If necessary 150–220 mg/m2/day acetazolamide or allopurinol: 8 mg/kg/ day can be used.
Intermediate dose of methotrexate therapy:                                        An intermediate and high-dose methotrexate therapy should not be 50–150 mg/m2 IV injection; no calcium folinate rescue required, given at          initiated when urinary pH values are below 7.0. The alkaline status of the 2–3 weeks intervals                                                               urine must be controlled at least during the first 24 h after initiation of
240 mg/m2 IV infusion over 24 h; calcium folinate rescue required, given          methotrexate administration (pH value ≥ 6.8).
at 4–7 days intervals                                                             Monitoring of methotrexate serum levels is mandatory immediately after 500–1000 mg/m2 IV infusion over 36–42 h; calcium folinate rescue required,        cessation of methotrexate administration, as well as 24 h, 48 h and 72 given at 2–3 weeks intervals                                                      h afterwards. On the basis of methotrexate serum levels, the occurrence of signs of toxicity can be inferred and the calcium folinate dosage can High-dose methotrexate therapy – calcium folinate rescue required:                be adjusted.
1–12 gm/m2 IV over 1–6 hours, given at 1–3 weeks intervals                        During the intrathecal administration systemic side effects may occur.
A careful clinical examination of the patients, particularly inspection of the For intrathecal or intraventricular methotrexate therapy a maximum dose           oral cavity, pharynx and larynx for changes in mucosa, regular monitoring of of 15 mg/m2 is administered.                                                      leucocytes and thrombocytes (daily up to 3 times weekly), complete blood Intrathecal route of administration: 0.2–0.5 mg/kg or 8–12 mg/m2                  count (once weekly), renal and liver functions should be performed.
methotrexate is administered every 2–3 days, after disappearance of the           During long-term or high-dosage therapy, bone marrow biopsies may be symptoms at weekly intervals, and subsequently at monthly intervals until         necessary.
CSF findings return to normal. Prophylactic intrathecal instillation should In severe leucopenia the risk of an infection should be borne in mind. In case be carried out every 6–8 weeks.
of infection, therapy should be stopped and appropriate antibiotic therapy should be instituted. In severe cases of myelosuppression the transfusion In severe, generalized, therapy-resistant psoriasis vulgaris including of blood, leucocytes and thrombocytes may be necessary.
psoriatic arthritis and other autoimmunopathies:
It is recommended that a test dose of 5-10 mg may be parenterally                 Drug Interactions administered one week prior to initiation of therapy, in order to detect idiosyncratic adverse effects. The recommended initial dose is 7.5 mg             Several drugs may cause interactions (mainly pharmacokinetic) during methotrexate once weekly. The dose should be increased as necessary but           concomitant administration of methotrexate.
should not exceed a maximum weekly dose of 25 mg of methotrexate.
The activity of methotrexate is increased by:
Dosage should be adjusted according to the general condition of the
Inhibition of the renal excretion of methotrexate with non-steroidal anti- patient.
inflammatory drugs, salicylates, sulphonamides, probenecid, cephalothin, Response to treatment can be expected after approximately 2-6 weeks.              penicillin, carbenicillin, ticarcillin, para-aminohippuric acid.
Once the desired therapeutic result has been achieved, dosage should be Drugs which are involved in the active tubular secretion impair the reduced gradually to the lowest possible effective maintenance dose.
elimination of methotrexate and therefore cause an increased plasma concentration.
In therapy-resistant rheumatoid arthritis:
The displacement of the methotrexate which is bound to plasma proteins Generally 7.5–15 mg methotrexate administered IM/SC initially, as a leads to a higher free concentration in the plasma, e.g. with salicylates, massive-dose therapy once weekly. Dosage can be increased by 2.5 mg sulfisoxazole, sulfafurazole, doxorubicin, bleomycin, cyclophosphamide, weekly, to a maximum of 25 mg weekly.
phenytoin, barbiturates, tranquilizers, tetracyclines, chloramphenicol, Response to treatment can be expected after approximately 4-8 weeks.              p-aminobenzoic acid, oral antidiabetics (chlorpropamide, amidopyrine Once the desired therapeutic result has been achieved, dosage should be           derivatives), diuretics.
reduced gradually to the lowest possible effective maintenance dose.
Increase of the intracellular accumulation of methotrexate and methotrexate In patients with impaired renal function the therapy risk should be               polyglutamates, e.g. with vinca alkaloids, epipodophyllotoxins, carefully considered and the dosage should be reduced correspondingly             probenecid.
if required.
The activity of methotrexate is decreased by:
Method of Administration                                                          Inhibition of the intracellular uptake of methotrexate (corticosteroids, Methotrexat “EBEWE” Pre-filled Syringe: Should be given IV, IM or                 L-asparaginase, bleomycin, penicillin); increase of the dihydrofolate SC.                                                                               reductase concentration (triamterene) or increase of the intracellular purine Use only clear and freshly prepared solutions.                                    concentration (allopurinol); vitamin preparations which contain folic acid or its derivatives (especially folinic acid).
Methotrexat “EBEWE” 50 mg can be administered IM, SC, IV (as bolus                Drugs with known hepatotoxicity should not be administered concomitantly injection or infusion), intra-arterially, intrathecally and intraventricularly.   with methotrexate due to increased risk of hepatoxicity.
Drugs with folic acid antagonist activity (pyrimethamine, trimethoprim) Methotrexat “EBEWE” 500 mg, 1000 mg and 5000 mg – concentrate may increase the toxicity of methotrexate.
for infusion has to be diluted with standard solutions for infusions before administration according to therapy protocol and duration of infusion. Use        The myelosuppressive activity can increase due to long-lasting pretreatment 5% glucose solution, Ringer’s lactate or physiological saline solution.           with myelosuppressive substances (e.g. sulphonamide, chloramphenicol, pyrazole derivatives, indomethacin, and diphenylhydantoin).
Generally 1–2% methotrexate solution is administered (in osteosarcoma higher concentrations are described in the literature).                           Methotrexate can enhance the activity of coumarin-like oral anticoagulants (the prothrombin time is prolonged due to a reduced decomposition of
These methotrexate solutions for infusion are stable at room temperature coumarin derivatives).
over 24 hours when exposed to light or protected from light. If longer infusion period is required, the infusion bags/bottle should be changed.          During simultaneous parenteral administration of acyclovir and intrathecal administration of methotrexate, neurological disorders can not be
Dosages higher than 100 mg/m are generally administered as IV
2 excluded.
infusion.
Methotrexate may impair the immunologic reaction to vaccinations and
Avoid contact with skin or mucosa.
may lead to severe complications. Therefore vaccinations should not be For single use only!                                                              carried out during methotrexate therapy.
According to the type and intensity of the myelosuppressive therapy of the Contraindications                                                                 disease and other factors the ability to respond normally to vaccination may
• Known hypersensitivity to any component of the drug                             take 3–12 months. Leukemia patients in remission should not be vaccinated
• Severe hepatic and renal impairment (serum creatinine > 2 mg%:                  with live vaccines at least 3 months after the last dose of methotrexate.