Special Warning : אזהרת שימוש

4.4. Special warnings and precautions for use
The prescriber should specify the day of intake on the prescription.

The prescriber should make sure patients understand that Methotrexate should only be taken once a week.

Patients should be instructed on the importance of adhering to the once-weekly intakes.

Warnings:
Methotrexate should be used with extreme caution in patients with hematological depression, renal impairment, peptic ulcer, ulcerative colitis, ulcerative stomatitis, diarrhea, debility and in young children and the elderly. (See 4.2).

Patients with pleural effusions or ascites should have these drained if appropriate before treatment or treatment should be withdrawn. A chest x-ray is recommended prior to initiation of methotrexate therapy or treatment should be withdrawn.

Conditions leading to dehydration such as emesis, diarrhea, stomatitis, can increase the toxicity of methotrexate due to elevated agent levels. In these cases, use of methotrexate should be interrupted until the symptoms cease.

It is important to identify patients with possibly elevated methotrexate levels within 48 hours after therapy, as otherwise methotrexate toxicity may be irreversible.
Symptoms of gastro-intestinal toxicity, usually first manifested by stomatitis, indicate that therapy should be interrupted otherwise hemorrhagic 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.

Particular caution should be exercised in the presence of inactive, chronic infections (e.g., herpes zoster, tuberculosis, hepatitis B or C), due to possible activation.

Methotrexate has some immunosuppressive activity and therefore the immunological response to concurrent vaccination may be decreased. In addition, concomitant use of a live vaccine could cause a severe antigenic reaction.

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 should be considered.

Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnea, 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 contract their doctor immediately should they develop persistent cough or dyspnea.

In addition, pulmonary alveolar hemorrhage has been reported with methotrexate used in rheumatologic and related indications. This event may also be associated with vasculitis and other comorbidities. Prompt investigations should be considered when pulmonary alveolar hemorrhage is suspected to confirm the diagnosis.

Methotrexate should be withdrawn from patients with pulmonary symptoms and a thorough investigation 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.

Special caution is required in patients with impaired pulmonary function.

Fertility
Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhea in humans during and for a short period after the discontinuation of treatment, affecting spermatogenesis and oogenesis during the period of its administration - effects that appear to be reversible on discontinuing therapy.

Teratogenicity – Reproductive risk

Methotrexate causes embryotoxicity, abortion and fetal malformations in humans. Therefore, the possible effects on reproduction, pregnancy loss and congenital malformations should be discussed with female patients of childbearing age (see section 4.6). In non-oncologic indications, the absence of pregnancy must be confirmed before Methotrexate is used. If women of a sexually mature age are treated, effective contraception must be used during treatment and for at least six months after.

For contraception advice for men see section 4.6.

Precautions:
Methotrexate should only be used by clinicians who are familiar with the various characteristics of the drug and its mode of action. Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, a chest x-ray, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests. This will include a routine examination of lymph nodes and patients should report any unusual swelling to the doctor.

Patients undergoing therapy should be subject to appropriate supervision every 2-3 months so that signs of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Renal function and full blood counts should be closely monitored before, during and after treatment.

Patients receiving low-dose methotrexate should:

Have a full blood count and renal and liver function tests before starting treatment. These should be repeated weekly until therapy is stabilised It is essential that the following laboratory tests are included regularly (every 2-3 months) in the clinical evaluation and monitoring of patients receiving methotrexate: complete hematological analysis, urinalysis, renal function tests, liver function tests and, when high doses are administered, determination of plasma levels of methotrexate.

Patients should report all symptoms and signs suggestive of infection, especially sore throat.

If acute methotrexate toxicity occurs, patients may require treatment with folinic acid.
Liver function tests

Treatment should not be initiated or should be discontinued if there are persistent or significant abnormalities in liver function tests, other non-invasive investigations of hepatic fibrosis, or liver biopsies.

Temporary increases in transaminases to two or three times the upper limit of normal have been reported in patients at a frequency of 13-20 %. Persistent elevation of liver enzymes and/or decrease in serum albumin may be indicative for severe hepatotoxicity. In the event of a persistent increase in liver enzymes, consideration should be given to reducing the dose or discontinuing therapy.

Histological changes, fibrosis and more rarely liver cirrhosis may not be preceded by abnormal liver function tests. There are instances in cirrhosis where transaminases are normal. Therefore, non-invasive diagnostic methods for monitoring of liver condition should be considered, in addition to liver function tests. Liver biopsy should be considered on an individual basis taking into account the patient's comorbidities, medical history and the risks related to biopsy. Risk factors for hepatotoxicity include excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family history of hereditary liver disorders, diabetes mellitus, obesity and previous contact with hepatotoxic drugs or chemicals and prolonged methotrexate treatment.

Additional hepatotoxic medicinal products should not be given during treatment with methotrexate unless clearly necessary. Alcohol consumption should be avoided (see sections 4.3 and 4.5). Closer monitoring of liver enzymes should be undertaken in patients concomitantly taking other hepatotoxic medicinal products.

Increased caution should be exercised in patients with insulin-dependent diabetes mellitus, as during methotrexate therapy, liver cirrhosis developed in isolated cases without any elevation of transaminases.

Pleuropulmonary manifestations of rheumatoid arthritis have been reported in the literature. In patients with rheumatoid arthritis, the physician should be specifically alerted to the potential for methotrexate induced adverse effects in the pulmonary system. Patients should be advised to contact their physicians immediately should they develop a cough or dyspnoea (see 4.8).

Haematopoietic 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 drug and appropriate supportive therapy (see 4.8). Patients should be advised to report all signs and symptoms suggestive of infection.
Systemic toxicity of methotrexate may also be enhanced in patients with renal dysfunction, ascites or other effusions due to prolongation of serum half-life.

Renal lesions may develop if the urinary flow is impeded and urinary pH is low, especially if large doses have been administered.

Reduce dose of methotrexate in patients with renal impairment.

In the presence of risk factors, such as – even borderline – impaired renal function, concomitant administration of non-steroidal anti-inflammatories is not recommended. Dehydration may also potentiate the toxicity of methotrexate.

High doses may cause the precipitation of methotrexate or its metabolites in the renal tubules. A high fluid throughput and alkalinisation of the urine to pH 6.5-7.0 by oral or intravenous administration of sodium bicarbonate (5x 625mgtablets every three hours) or acetazolamide (500mg orally four times a day) is recommended as a preventive measure.

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.

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

In paediatric population, radiation induced dermatitis and sunburn can reappear under methotrexate therapy(recall-reaction).

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose- galactose malabsorption should not take this medicine.

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