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Dosing in the treatment of rheumatoid arthritis, psoriasis and severe psoriatic arthritis: The patients should be informed clearly that in the treatment of rheumatoid arthritis, psoriasis or severe psoriatic arthritis the administration is once weekly.
The prescriber should specify the day of intake on the prescription.
The prescriber should make sure patients understand that methotrexate tablets should only be taken once a week. Patients should be instructed on the importance of adhering to the once-weekly intakes.
Warnings: Methotrexate should only be administered by physicians experienced in antimetabolite chemotherapy.
Concomitant administration of hepatotoxic or haematotoxic DMARDs (disease-modifying antirheumatic drug, e.g. leflunomide) is not advisable.
Due to the possibility of fatal or severe toxic reactions, the patient should be fully informed by the physician of the risks involved and be under constant supervision. 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.
Fertility and reproduction: Fertility: 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.
Teratogenicity - Reproductive risk: Methotrexate causes embryotoxicity, abortion and foetal malformations in humans. Therefore, the possible effects on reproduction, pregnancy loss and congenital malformations should be discussed with male and female patients of childbearing age. 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.
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.
Recommended examinations and safety measures: Before beginning treatment or resuming treatment after a recovery period: 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 B and C should be excluded.
During treatment: The tests as follows must be conducted weekly in the first two weeks, then every two weeks for a month; thereafter, depending on the leucocyte count and the stability of the patient, at least once a month during the next six months and then at least every three months. An increased monitoring frequency should be considered when the dose is increased. In particular, elderly patients should be monitored at short intervals for early signs of toxicity.
Examination of the mouth and throat for mucosal changes.
Complete blood count with differential blood count and platelets. Methotrexate-induced hematopoietic suppression may occur abruptly and with apparently safe dosages. Any serious decrease in leucocyte or platelet counts indicates the immediate discontinuation of treatment and appropriate supportive therapy. Patients should be encouraged to report all signs and symptoms suggestive of infection to their doctor. In patients simultaneously taking hematotoxic medicinal products (e.g. leflunomide), blood count and platelets should be closely monitored.
Liver function tests: Particular attention should be given to the appearance of liver toxicity. Treatment should not be initiated or should be discontinued if there are persistent or significant abnormalities in liver function tests, other noninvasive 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. Closer monitoring 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.
Renal function: Should be monitored by renal function tests and urinalysis. 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. Treatment with moderately high and high doses of methotrexate should not be initiated at urinary pH values of less than 7.0. Alkalinization 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.
Respiratory tract examination: Patients must be monitored for symptoms of a lung function disorder and lung function tests performed if necessary. Lung-related symptoms (particularly a dry, non-productive cough) or non-specific pneumonitis that occurs during treatment with methotrexate can be a sign of potentially dangerous damage and require the discontinuation of treatment and careful monitoring. Although the clinical presentation is variable, patients with methotrexate-induced lung diseases typically suffer from fever, cough, dyspnoea, or hypoxemia. A chest X-ray must be taken to be able to exclude an infection. Acute or chronic interstitial pneumonia, often in association with blood eosinophilia, may occur and deaths have been reported. Patients should be informed of the risks of pneumonia and advised to contact their doctor immediately if they develop a persistent cough or persistent dyspnoea.
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 discontinued in patients with pulmonary symptoms and an immediate examination (including chest X-ray) should be performed to exclude infection and tumors. 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 rapid diagnosis and discontinuation of methotrexate therapy. 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).
Opportunistic infections can occur during treatment with methotrexate, including Pneumocystis jirovecii pneumonia, which can also have a fatal outcome. If a patient develops pulmonary symptoms, the possibility of Pneumocystis jirovecii pneumonia should be considered.
Particular caution is required in patients with impaired pulmonary function.
Particular caution is also required in the presence of inactive chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) as it is possible that activation of these infections may occur.
Renal impairment and patients at risk of renal impairment: 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, that cause kidney damage (e.g. NSAIDs) or that can potentially lead to impairment of hematopoiesis, 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. (See renal function as previously mentioned).
Immune system: Due to its effect on the immune system, methotrexate may impair the response to vaccinations and affect the results of immunological tests. Concurrent vaccination using live vaccines should not be given.
Malignant lymphomas: Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. If the lymphomas fail to regress spontaneously, cytotoxic treatment must be initiated.
Pleural effusions or ascites: Pleural effusions and ascites should be drained before initiation of methotrexate treatment.
Conditions that cause dehydration such as vomiting, diarrhea or stomatitis: Conditions that cause dehydration such as vomiting, diarrhea or stomatitis can increase toxicity as a result of raised active substance levels. In this case, treatment with methotrexate must be discontinued until the symptoms have disappeared.
It is important to determine any increase in active substance levels within 48 hours of therapy, otherwise irreversible methotrexate toxicity may occur.
Diarrhea and ulcerative stomatitis may be signs of toxic effects and require the discontinuation of treatment, otherwise, hemorrhagic enteritis and death from intestinal perforation may occur. Following the occurrence of haematemesis, black-colored stools or blood in the stools, treatment must be discontinued.
Folic acid supplementation: 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.
Vitamin products: Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate.
Dermatitis and sunburn: Radiation-induced dermatitis and sunburn can reappear during methotrexate therapy (recall reactions). Psoriatic lesions can worsen during UV radiation and co-administration of methotrexate.
Skin toxicity: 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.
Encephalopathy/leukoencephalopathy: 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.
Progressive multifocal leukoencephalopathy (PML): Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients using methotrexate, mostly in combination with other immunosuppressive agents. PML can be fatal and should be considered in the differential diagnosis of immunosuppressed patients presenting with new or worsening neurological symptoms.
Lactose excipient warning: This medication contains lactose. Patients with rare hereditary conditions such as 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 has a minor or moderate influence on the ability to drive and use machines.
Use in Pregnancy & Lactation: See Use in Pregnancy & Lactation section for further information.
