Special Warning : אזהרת שימוש

4.4 Special Warnings and Precautions for Use
Patients must be clearly informed, that Methotrexat "Ebewe" must be administered once a week.
Patients undergoing therapy should be subject to appropriate supervision so that signs of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay.
Therefore, methotrexate should only be administered by, or under the supervision of, physicians whose knowledge and experience includes the use of antimetabolite therapy.
Because of the possibility of severe or even fatal toxic reactions, the patient should be fully informed of the risks involved and the recommended safety measures. However, doses exceeding 20 mg/week can be associated with significant increase in toxicity, especially bone marrow suppression.
Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy. In addition, methotrexate causes embryotoxicity, abortion and foetal defects in humans. Therefore, the possible risks of effects on reproduction should be discussed with patients of childbearing potential (see section 4.6).
Recommended examinations and safety measures:
Before beginning methotrexate therapy or re-instituting methotrexate therapy: Complete blood count with differential blood count and platelets, liver enzymes, bilirubin, serum albumin, chest x-ray and renal function tests. If clinically indicated, tuberculosis and hepatitis should be excluded.
During therapy (at least once a month during the first six months and every three months thereafter): An increased monitoring frequency should be considered also when the dose is increased.
a. Examination of the mouth and throat for mucosal changes.
b. Complete blood count with differential blood count and platelets. Haemopoietic suppression caused by methotrexate may occur abruptly and with apparently safe dosages. Any profound drop in white-cell or platelet counts indicates immediate withdrawal of the medicinal product and appropriate supportive therapy. Patients should be advised to report all signs and symptoms suggestive of infection. Patients simultaneously taking haematotoxic medicinal products (e.g., leflunomide) should be monitored closely for blood count and platelets.
c. Liver function tests: Particular attention should be given to the appearance of liver toxicity. Treatment should not be instituted or should be discontinued if any abnormality of liver function tests, or liver biopsy, is present or develops during therapy. Such abnormalities should return to normal within two weeks after which treatment may be recommenced at the discretion of the physician. There is no evidence to support use of a liver biopsy to monitor hepatic toxicity in rheumatological indications.
For psoriasis patients the need for a liver biopsy prior to and during therapy is controversial. Further research is needed to establish whether serial liver chemistry tests or propeptide of type III collagen can detect hepatotoxicity sufficiently. The evaluation should be performed case by case and differentiate between patients with no risk factors and patients with risk factors such as excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family history of inheritable liver disease, diabetes mellitus, obesity, and history of significant exposure to hepatotoxic drugs or chemicals, and prolonged methotrexate treatment or cumulative doses of 1.5 g or more.
Monitoring of liver enzymes in serum: Temporary increases in transaminases to twice or three times of the upper limit of normal have been reported by patients at a frequency of 13–20%. In the case of a constant increase in liver enzymes, a reduction of the dose or discontinuation of therapy should be taken into consideration.
Due to its potentially toxic effect on the liver, additional hepatotoxic medicinal products should not be taken during treatment with methotrexate unless clearly necessary, and the consumption of alcohol should be avoided or minimized (see 4.5). Closer monitoring of liver enzymes should be exercised in patients taking other hepatotoxic medicinal products concomitantly (e.g., leflunomide). This is also required during simultaneous administration of haematotoxic medicinal products (e.g., leflunomide).
d. Renal function should be monitored by renal function tests and urinanalysis (see also 4.2 and 4.3): As methotrexate is eliminated mainly by renal route, increased serum concentrations are to be expected in the case of renal insufficiency, which may result in severe undesirable effects.
Where renal function may be compromised (e.g., in the elderly), monitoring should take place more frequently. This applies in particular, when medicinal products are administered concomitantly, which affect the elimination of methotrexate, cause renal damage (e.g., non-steroidal anti-inflammatory medicinal products) or which can potentially lead to impairment of blood formation. Dehydration may also intensify the toxicity of methotrexate.
e. Respiratory system: Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea, cough (especially a dry non-productive cough) and fever for which patients should be monitored at each follow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop persistent cough or dyspnoea.
Methotrexate should be withdrawn in patients with pulmonary symptoms and a thorough investigation (including chest x-ray) should be made to exclude infection. If methotrexate- induced lung disease is suspected, treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.
Pulmonary symptoms require a quick diagnosis and discontinuation of methotrexate therapy. Pneumonitis can occur at all dosages.
f. Methotrexate may, due to its effect on the immune system, impair the response to vaccination and affect the results of immunological tests. Particular caution is also needed in the presence of inactive, chronic infections (e.g., herpes zoster, tuberculosis, hepatitis B or C) due to possible activation. Concurrent vaccination using live vaccines should not be carried out .
Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires the initiation of cytotoxic therapy.
Pleural effusions and ascites should be drained prior to initiation of methotrexate treatment.
Diarrhoea and ulcerative stomatitis can be toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.
Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate.
g. Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety are available for this population (see section 4.2).
Radiation-induced dermatitis and sunburn can reappear under methotrexate therapy (recall-reaction). Psoriatic lesions can exacerbate during UV-irradiation and simultaneous administration of methotrexate.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose and is essentially “sodium-free”.

Effects on Driving

4.7 Effects on Ability to Drive and Use Machines
Central nervous symptoms such as tiredness and dizziness can occur during treatment, Methotrexat “Ebewe” has minor or moderate influence on the ability to drive and use machines.