Trexan Special Precautions

Methotrexate must be used only by physicians experienced in antimetabolite chemotherapy.
Patients must be appropriately monitored during treatment so that signs of possible toxic effects or adverse reactions can be detected and evaluated with minimal delay.
Especially strict monitoring of the patient is indicated following prior radiotherapy (especially of the pelvis), functional impairment of the haematopoietic system (e.g., following prior radio- or chemotherapy), impaired general condition as well as advanced age and in very young children.
Because of the possibility of severe or even fatal toxic reactions, patients should be extensively informed by the treating doctor of the risks involved (including early signs and symptoms of toxicity) and the recommended safety measures. Patients should be informed that they must notify the doctor immediately if any symptoms of an overdose occur and that the symptoms of the overdose need to be monitored (including regular laboratory tests).
Doses exceeding 20 mg week can be associated with a substantial increase in toxicity, especially bone marrow depression.
Because of the delayed excretion of methotrexate in patients with impaired kidney function, they should be treated with particular caution and only with low doses of methotrexate (see Dosage & Administration and Contraindications).
Methotrexate should be used only with great caution, if at all, in patients who have a significant liver disease, particularly if this is/was alcohol-related (see Dosage & Administration and Contraindications).
Skin and mucosal contact with methotrexate injection solution is to be avoided.
Concomitant use of hepatotoxic or haematotoxic DMARDs (disease-modifying antirheumatic drugs, e.g. leflunomide) is not advisable.
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 Methotrexate should be withdrawn from patients with pulmonary symptoms and a thorough investigation (including chest X-ray) undertaken to exclude infection and tumours. If methotrexate induced lung disease is suspected, treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.
Methotrexate-induced lung diseases such as pneumonitis can occur acutely and at any time during treatment, are not always completely reversible and have already been observed at all doses (including low doses of 7.5 mg/week).
For the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, but only when diagnosis has been established by biopsy and/or after dermatological consultation.
Deaths have been reported in association with the use of methotrexate in the treatment of psoriasis.
Methotrexate should be used with extreme caution in the presence/history of infection, peptic ulcer, ulcerative colitis, debility, and in extreme youth and old age. Use in patients with active gastrointestinal ulcer disease is contraindicated. If profound leukopenia occurs during therapy, bacterial infection may occur or become a threat. Cessation of the drug and appropriate antibiotic therapy is usually indicated. In severe bone marrow depression blood or platelet transfusions may be necessary.
Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.
Following the occurrence of haematemesis, black coloured stools or blood in the stools, treatment must be discontinued.
In addition other conditions leading to dehydration such as emesis, can increase the toxicity of methotrexate due to elevated levels of the active substance. In these cases use of methotrexate should be interrupted until symptoms cease. It is important to determine any increase in active substance levels within 48 hours of therapy, otherwise irreversible methotrexate toxicity may occur.
Because of the possibility of severe and even life-threatening toxic reactions the patient should be fully informed by the attending physician of the risks involved before onset of methotrexate treatment. The patient should be closely monitored throughout the treatment.
Patients should be informed of the signs and symptoms of toxicity, of the need to see their physician promptly if they occur, and the need for close follow-up, including regular laboratory tests for monitoring toxicity.
It should be emphasized to the patient treated for psoriasis that the recommended dose must be taken only once a week. The prescriber should specify the day of intake on the prescription. Patients should be instructed on the importance of adhering to the once-weekly intakes, and that mistaken daily use of the recommended dose has led to fatal toxicity (see Dosage & Administration and Overdosage).
Most adverse reactions are reversible if detected early. When adverse reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this includes the use of calcium folinate and/or acute, intermittent haemodialysis with high-flux dialyzer.
Methotrexate should be used with extreme caution in patients with psychiatric disorders. Patients with pleural effusions and ascites should be drained prior to initiation of methotrexate therapy or treatment should be withdrawn.
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 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, thereafter patients should be monitored every 2-3 months throughout treatment; Patients should report all symptoms and signs suggestive of infection, especially sore throat. Any infections should be attended to, before initiation of methotrexate therapy.
Haematopoietic suppression caused by methotrexate may occur abruptly and with apparently safe dosages. Full blood counts should be closely monitored before, during and after treatment. If a clinically significant drop in white cell or platelet count develops, methotrexate therapy should be withdrawn immediately and appropriate supportive therapy given (see Adverse Reactions). Patients should be advised to report all symptoms or signs suggestive of infection. Any infections should be attended before initiation of methotrexate therapy.
Methotrexate may be hepatotoxic, particularly at high doses or with prolonged therapy. Liver atrophy, necrosis, cirrhosis, fatty changes and periportal fibrosis have been reported. Risk factors for severe liver damage are e.g. previous liver disease, repeatedly abnormal liver function tests and alcohol consumption. Additional hepatotoxic medicinal products should not be taken during the treatment with methotrexate unless clearly necessary and the consumption of alcohol should be avoided or clearly reduced (see Interactions).
Diabetic patients who are treated with insulin have increased risk for liver toxicity.
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.
Check of liver-related 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-related enzyme, a reduction of the dose or discontinuation of therapy should be taken into consideration. Closer monitoring of liver enzymes is necessary especially in patients taking other liver- or haematotoxic medicinal products (e.g. leflunomide). Further research is needed to establish whether serial liver function tests or determinations of propeptide of type III collagen are appropriate for detecting hepatotoxicity.
Patients with risk factors: These primarily include: anamnestic alcohol abuse; persistent increase in liver enzymes; anamnestic hepatopathy including chronic hepatitis B or C; familial anamnesis with hereditary hepatopathy and secondarily (with possibly lower relevance): diabetes mellitus; adiposity; anamnestic exposure to hepatotoxic medicines or chemicals.
The need of liver biopsy should be evaluated case by case and national recommendations should be followed.
Kidneys: Methotrexate therapy in patients with impaired renal function should be undertaken with extreme caution because impairment of renal function will decrease methotrexate elimination. Impaired renal function may result in methotrexate accumulation in toxic amount or even in additional renal damage. In patients with renal impairment the dose of methotrexate should be reduced.
Renal function should be monitored by renal function tests and urinalyses. If serum creatinine levels are increased, the dose should be reduced. If creatinine clearance is less than 30 ml/min, treatment with methotrexate should not be given. If creatinine clearance is less than 60 ml/min, methotrexate doses >100 mg/m² not be given (see Dosage & Administration and Contraindications).
Treatment with methotrexate doses of >100 mg/m² should not be initiated at urinary pH values of less than 7.0. Alkalinisation of the urine must be tested by repeated pH monitoring (value greater than or equal to 6.8) for at least the first 24 hours after the administration of methotrexate is started.
Renal lesions may develop if the urinary flow is impeded and urinary pH is low, especially if large doses have been administered.
Methotrexate may cause renal damage that may lead to acute renal failure. Close attention to renal function including adequate hydration, urine alkalinization by oral or intravenous administration of sodium bicarbonate (5 x 625 mg tablets every three hours) or acetazolamide (500 mg orally four times a day), and measurement of serum methotrexate and renal function are recommended.
As methotrexate is eliminated mainly via the kidneys, increased concentrations are to be expected in the presence of renal impairment, which may result in severe adverse reactions.
If there is the possibility of renal impairment (e.g. in elderly subjects), monitoring should take place at shorter intervals. This applies in particular when medicinal products that affect the elimination of methotrexate, or that cause kidney damage (e.g. NSAIDs) or that can potentially lead to impairment of haematopoiesis, are administered concomitantly.
If risk factors such as renal function disorders, including mild renal impairment, are present, combined administration with NSAIDs is not recommended. Dehydration may also intensify the toxicity of methotrexate.
Concomitant use of proton pump inhibitors (PPIs) and high dose methotrexate should be avoided, especially in patients with renal impairment.
Immune system: Methotrexate has some immunosuppressive activity and immunological responses to concurrent vaccination may be decreased. Vaccination with live vaccines is contra-indicated during the therapy.
The immunosuppressive effect of methotrexate should be taken into account when immune responses of patients are important or essential. Special attention should be paid in cases of inactive chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) because of their potential activation.
Methotrexate may trigger tumour lysis syndrome in patients with rapidly growing tumour.
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.
Since cases of encephalopathy/leukoencephalopathy have occurred in cancer patients treated with methotrexate, this cannot be ruled out either for patients with non-cancer indications.
The disappearance of methotrexate from plasma should be monitored, if possible. This is recommended in particular when high, or very high doses are administered in order to permit calculation of an adequate dose of leucovorin (folinic acid) rescue.
Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
In the treatment of rheumatoid arthritis, acetylsalicylic acid, nonsteroidal anti-inflammatory (NSAID) agents, and/or low dose steroids can be continued, although concomitant use of NSAIDs and methotrexate may be associated with an increased risk of toxicity. Steroids may be gradually reduced in patients responsive to methotrexate.
The interactions of methotrexate and other antirheumatic drugs such as gold, penicillamine, hydroxychloroquine, sulfasalazine or cytotoxic agents have not been studied comprehensively, and concurrent use may increase the incidence of adverse reactions.
Concomitant administration of folate antagonists such as trimethoprim/sulfamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.
In addition, pulmonary alveolar haemorrhage 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 haemorrhage is suspected to confirm the diagnosis.
If acute methotrexate toxicity occurs, patients may require treatment with folinic acid. In patients with rheumatoid arthritis or psoriasis, folic acid or folinic acid supplementation may reduce methotrexate toxicity, such as gastrointestinal symptoms, stomatitis, alopecia and elevated liver enzymes.
It is recommended to check levels of vitamin B12 prior to initiating folic acid supplementation, particularly in adults aged over 50 years, as folic acid intake may mask a vitamin B12 deficiency.
Methotrexate may cause adverse urinary tract reactions, such as cystitis and haematuria.
Radiation induced dermatitis and sun-burn can reappear under methotrexate therapy (recall reaction). Psoriatic lesions can exacerbate during UV-irradiation and simultaneous administration of methotrexate.
Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis (Lyell's syndrome) or Stevens-Johnson syndrome have been reported after single or multiple doses of methotrexate.
Trexan 2.5 mg tablets contain lactose and patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on ability to drive and use machines: Central nervous system symptoms, such as fatigue and dizziness, can occur during treatment with methotrexate which may have minor or moderate influence on the ability to drive and use machines.
Use in Pregnancy: Methotrexate has been shown to be teratogenic - reproductive risk; it causes embryotoxicity, abortion and foetal malformations in humans.
Therefore, the possible effects on reproduction, pregnancy loss and congenital malformations should be discussed with female patients of childbearing age (see Use in Pregnancy & Lactation).
In non-oncologic indications, the absence of pregnancy must be confirmed before methotrexate tablet 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 Use in Pregnancy & Lactation.
If this drug is used during pregnancy for antineoplastic indications, or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the foetus.
Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea 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.