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  • Methotrexate
    / Pfizer


    Active Ingredient
    Methotrexate 2.5 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Tablets

    100 x 2.5 mg

    full basket chart 13106

    Related information


    Dosage

    Psoriasis: Recommended started dose is 2.5 mg three times with a 12 hours interval as a weekly treatment or 7.5 mg as a single dose once a week.
    Rheumatoid arthritis: Starting dose is 7.5 mg as a single dose once a week. For both dosage schedules: A therapeutic effect is usually obtained within 6 weeks and continues to increase thereafter over the next 12 weeks or longer. If a therapeutic effect is not obtained after 6-8 weeks, the dose can be increased in increments of 2.5 mg per week. Optimal weekly dose is usually within the range 7.5 – 15 mg and the dose should not exceed 20 mg/week. If no response is obtained after 8 weeks at the maximum dose, the treatment should be discontinued. When the treatment is effective, the maintenance dose should be kept at lowest possible. The optimal treatment duration is still not known, but preliminary information suggests that the effect initially obtained may last for at least 2 years with the maintenance dose. If treatment is suddenly discontinued, the symptoms may return within 3-6 weeks.
    Cytotoxic drugs: Dosage up to 30 mg/m2 may be administered orally but higher doses shall be given as injection or infusion. Oral treatment in doses of up to 20 mg/m2/weekly is used, as well as intravenous administration and as a prophylactic intrathecally in maintenance treatment for acute lymphatic leukaemia in children.


    Indications

    Antineoplastic chemotherapy, psoriasis. Rheumatoid arthritis. Methotrexate can be used in the treatment of selected adults with rheumatoid arthritis, only when the diagnosis has been well established according to rheumatological standards, with inadequate response to other forms of antirheumatic therapy.


    Contra-Indications

    Hypersensitivity to methotrexate, or any of the other excipients. Stop breast-feeding while undergoing treatment with methotrexate. Anti-rheumatic and psoriasis drugs: Alcoholism, alcoholic liver disease or other chronic liver disease. Bone marrow hypoplasia with leukopenia, thrombocytopenia or significant anaemia. Severe infections. Rheumatoid lung disease and other lung diseases. Visible or quantifiable evidence of immunodeficiency. Pregnancy.


    Special Precautions

    Fatal toxicities related to inadvertent daily rather than weekly dosing have been reported, particularly in elderly patients. It should be emphasized to the patient that the recommended dose is taken weekly for rheumatoid arthritis and psoriasis.Because of the possibility of serious toxic reactions (which can be fatal), methotrexate should be used only in life threatening neoplastic diseases, or in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease that is not adequately responsive to other forms of therapy. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Because of the possibility of severe toxic reactions, the patient should be informed by the physician of the risks involved in the treatment and should be under a physician’s constant supervision. Insulin-dependent diabetes is a risk factor for worsening of liver function. Methotrexate has been reported to cause foetal death and/or congenital anomalies. It is not recommended for the treatment of neoplastic diseases in women of childbearing age, unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks. Methotrexate affects spermatogenesis and oogenesis while administered and that can decrease fertility. This effect can be reversible when treatment is stopped. As with other cytotoxic drugs, methotrexate may induce tumor lysis syndrome in patients with rapidly growing tumours. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication. Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anaemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high doses) and NSAIDs. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis. Methotrexate is excreted slowly from accumulated fluid (e.g. pleural effusions, ascites). This results in a prolonged terminal half-life and unexpected toxicity. In patients with significant fluid accumulations, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels. Methotrexate therapy in patients with impaired renal function should be undertaken with extreme caution and the dose must be reduced since the impairment of renal function will decrease methotrexate elimination. It should be emphasized to the patient that the recommended dose is taken weekly for the treatment of rheumatoid arthritis and psoriasis and that doses taken daily by mistake could lead to severe toxicity. Folate deficiency may increase the risk of methotrexate toxicity. Patients with rare hereditary problems such as galactose intolerance, the Lap lactase deficiency or glucose-galactose malabsorption should not take this medicine.
    Organ system toxicity
    Lymphomas: Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted.
    Hematologic: Methotrexate can suppress haematopoiesis and cause anaemia, aplastic anaemia, pancytopenia, leukopenia, neutropenia and/or thrombocytopenia. Methotrexate should be used with caution, if at all, in patients with malignancy and pre-existing hematopoietic impairment. In the treatment of neoplastic diseases, methotrexate should be continued only if the potential benefit outweighs the risk of severe myelosuppression. In rheumatoid arthritis, methotrexate should be stopped immediately if there is a significant drop in blood cell counts.
    Pulmonary: Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis may occur at any time during therapy. This has been reported at low doses. It is not always fully reversible. Fatalities have been reported. Pulmonary signs or symptoms, e.g., a dry unproductive cough, fever, cough, chest pain, dyspnoea, hypoxemia, and an infiltrate on chest X-ray, or a nonspecific pneumonitis occurring during methotrexate therapy, may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Pulmonary lesions can occur at all dosages. Infection (including pneumonia) needs to be excluded.
    Gastrointestinal: If vomiting, diarrhoea, or stomatitis occur, resulting in dehydration, methotrexate should be discontinued until patient has recovered. Hemorrhagic enteritis can occur and may be fatal due to intestinal perforation. Methotrexate should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis.
    Hepatic: Methotrexate has the potential for acute hepatitis and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally two years or more) and after a total cumulative dose of at least 1.5 grams. In studies in psoriatic patients, hepatotoxicity appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes, and advanced age. Transient abnormalities of liver parameters are observed frequently after methotrexate administration and are usually not a reason for modification of methotrexate therapy. Persistent liver abnormalities, and/or decrease of serum albumin may be indicators of serious liver toxicity. Methotrexate has caused reactivation of hepatitis B infection or worsening of hepatitis C infections, in some cases resulting in death. Some cases of hepatitis B reactivation have occurred after discontinuation of methotrexate. Clinical and laboratory evaluation should be performed to evaluate pre-existing liver disease in patients with prior hepatitis B or C infections. Based on these evaluations, treatment with methotrexate may not be appropriate for some patients.
    Renal: Methotrexate may cause renal damage that may lead to acute renal failure. Therefore close attention to renal function including is recommended with methotrexate treatment.
    Skin: Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis (Lyell’s Syndrome), Stevens-Johnson syndrome, and erythema multiforme, have been reported within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration, after single or repeated doses. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be worse by the use of methotrexate.
    Central nervous system: There have been reports of leukoencephalopathy in patients receiving methotrexate. Cases of severe neurological adverse reactions that ranged from headache to paralysis, coma and stroke-like episodes have been reported mostly in juveniles and adolescents given methotrexate in combination with cytarabine.
    Infection or Immunologic States: Methotrexate should be used with extreme caution in the presence of active infection, and is usually contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes. Pneumonia (in some cases leading to respiratory failure) may occur. Potentially fatal opportunistic infections, including Pneumocystis carinii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered.
    Immunization: Immunization may be ineffective when given during methotrexate therapy. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated vaccinia infections after smallpox immunization in patients receiving methotrexate therapy.
    Monitoring of treatment: Patients undergoing methotrexate therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, liver function test, hepatitis B and C tests; renal function tests and a chest x-ray. Methotrexate treatment shall be discontinued temporarily in case of infections, thrombocytopenia, leukopenia, and impaired renal functions. If liver enzyme values will be two times higher than the reference values, methotrexate treatment shall be stopped until they are normal again.
    NSAIDs and psoriasis medications: The patient shall be informed of risk and they should be under constant physician with methotrexate treatment. Before the treatment is started, an experimental dose of 2.5 mg can be administered. A complete blood exam shall be performed after one week of treatment and then at least once montly and tests for liver enzymes and renal function every one to two months. More frequent monitoring is usually indicated during anti-neoplastic therapy, initial or change in dosing, or during periods of increased risk of elevated methotrexate blood levels (e.g. dehydration), For psoriasis, liver damage should be checked and liver function tests performed, including serum albumin and prothrombine time, before treatment is started. Liver function tests are often normal during the development of fibrosis and cirrhosis. This damage may only been detected by tissue biopsy. It is recommended that liver samples be taken: 1) before the treatment is initiated or shortly thereafter (within 2-4 months), 2) when a cumulative dose totals 1.5 gram and 3) after additional 1-1,5 grams. In the event of cirrhosis or extensive fibrosis, treatment shall be stopped. For mild fibrosis, a biopsy needs to be repeated after 6 months. Minor histologic changes, such as changes in fat and mild porta hapetis inflammation are relatively common before treatment is started. Even though these changes do not indicate that methotrexate treatment should be avoided or stopped, the drug must be used carefully.
    In rheumatoid arthritis patients, age at first use of methotrexate and the duration of therapy have been reported as risk factors for hepatotoxicity. Persistent abnormalities in liver function tests may precede appearance of fibrosis and cirrhosis in patients with rheumatoid arthritis. Liver function tests should be performed at baseline and at 4 – 8 week intervals in patients receiving methotrexate for rheumatoid arthritis. Pretreatment liver biopsy should be performed for patients with a history of excessive alcohol consumption, persistently abnormal baseline liver function test values, or chronic hepatitis B or C infection. During therapy, a liver biopsy should be performed if there are persistent liver function test abnormalities, or there is a decrease in serum albumin below the normal range. If the results of a liver biopsy show mild changes (Roenigk grades I, II, IIIa), methotrexate may be continued and the patient monitored according to the recommendations listed above. Methotrexate should be discontinued in any patient who displays persistently abnormal liver function tests and refuses liver biopsy, or in any patient whose liver biopsy shows moderate to severe changes (Roenigk grade IIIb or IV). Perform an x-ray of the lungs before methotrexate treatment is started and if changes caused by methotrexate is suspected. Continue treatment with acetylsalicylic acid, NSAIDs and/or steroids in low doses, but carefully. The use of steroids shall be discontinued gradually in patient responding to methotrexate treatment.
    Cytostatic agents: Toxicity of methotrexate can occur, even with low doses and therefore it is important to monitor patients. Most side effects are reversible if they are detected soon. At sign of leukopenia it is recommended to stop treatment temporarily. As methotrexate can cause hepatic damages and elimination is mainly renal, hepatic and renal function should be monitored regularly. If necessary, bone marrow sample should be taken. Due to diminished hepatic and renal function as well as decreased folate stores in elderly patients, relatively low doses should be considered and these patients should be closely monitored for early signs of toxicity.


    Side Effects

    The incidence and severity of acute side effects are related to dose and frequency of administration, but side effects have occurred at all doses and they can occur when ever during the treatment. Most adverse events are reversible if methotrexate treatment is stopped. If methotrexate treatment is reinitiated it should be done with care after thorough evaluation on the need for the product. Occurrence of toxicity should be monitored carefully.  The most frequently reported adverse reactions include stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness, and decreased resistance to infection.
    For full details see prescribing information.


    Drug interactions

    Vaccines, salicylates, propionic acid, NSAIDs, ketorolac, oral hypoglycemics, phenytoin, tetracycline, sulphonamides, chloramphenicol, thiazides. Folic acid, anticonvulsants, co-trimoxazole, pyrimethamine, sulphasalazine, trimethoprim. Acitretin nephrotoxic or helaptoxic drugs, cyclosporin.
    For full details see prescribing information.


    Pregnancy and Lactation

    Methotrexate can cause foetal death, embryotoxicity, abortion or teratogenic effects when administered to a pregnant woman. During pregnancy, and particularly during the first three months, cytostatics should only be given on the basis of strict indications and after the mother’s needs have been weighed up against the risks for the foetus. Treatment with methotrexate during the first three months has resulted in a high frequency of deformities (especially cranium and deformities of the extremities). Women of childbearing potential should not be started on methotrexate until pregnancy is excluded and should be fully counselled on the serious risk to the foetus should they become pregnant while undergoing treatment. Pregnancy should be avoided if either partner is receiving methotrexate as this can affect spermatogenesis in males. The optimal time interval between the cessation of methotrexate treatment of either partner and pregnancy has not been clearly established. In published data, the recommended time is from three months to one year. Methotrexate is excreted in breast milk in such quantities that there is a risk of effects on the breastfeeding infant, even at therapeutic doses. Therefore breastfeeding should be stopped before methotrexate is started.


    Overdose

    Overdose experience with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose has also been reported. Reports of oral overdose indicate accidental daily administration instead of weekly. Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions such as leukopenia, thrombocytopenia, anaemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anaemia were also reported.
    Recommended treatment:
    Antidote treatment: Administer parenteral folic acid at dosages either equal to or greater than the inadvertently administered methotrexate dose and preferably within one hour. Folic acid is recommended to prevent toxicity and to act against the effect of the methotrexate overdose. Folic acid administration shall start as soon as possible. As the time interval between methotrexate administration and folic acid initiation increases, the effectiveness of folic acid in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment. In case of massive overdose, hydration and urinary alkalinisation may be necessary to prevent the precipitation of the drug and/or its metabolites in the renal tubes. Neither standard haemodialysis nor peritoneal dialysis has been shown to increase methotrexate elimination. Repeated haemodialysis may be attempted in the event of methotrexate overdose, where high-flux filters are used.


    Manufacturer
    Haupt Pharma GmbH
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