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METHOTREXATE is a brand name for Methotrexate. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Methotrexate is indicated in the treatment of neoplastic disease, such as trophoblastic neoplasms and leukaemia, and the symptomatic treatment of severe recalcitrant disabling psoriasis which is not adequately responsive to other forms of therapy.
Verbatim from this product's MHRA label. Tap a section to expand.
Methotrexate should only be prescribed by physicians with expertise in the use of methotrexate and a full understanding of the risks of methotrexate therapy. The prescriber should ensure that patients or their carers will be able to comply with the once weekly regimen.
Important warning about the dosage of Methotrexate In the treatment of psoriasis, Methotrexate must only be used once a week. Dosage errors in the use of Methotrexate can result in serious adverse reactions, including death. Please read this section of the summary of product characteristics very carefully.
Adults and children Antineoplastic Chemotherapy Methotrexate is active orally and parenterally. Methotrexate Injection may be given by the intramuscular, intravenous, intraarterial or intrathecal routes.
Note:
Only the 50 mg/2 ml presentation should be used for the intrathecal route of administration to prevent accidental overdose. Dosage is related to the patient's body weight or surface area. Methotrexate has been used with beneficial effect in a wide variety of neoplastic diseases, alone and in combination with other cytotoxic agents.
Choriocarcinoma and Similar Trophoblastic Diseases Methotrexate is administered orally or intramuscularly in doses of 15-30 mg daily for a 5 day course. Such courses may be repeated 3-5 times as required, with rest periods of one or more weeks interposed between courses until any manifesting toxic symptoms subside.
The effectiveness of therapy can be evaluated by 24 hours quantitative analysis of urinary chorionic gonadotrophin hormone (HCG). Combination therapy with other cytotoxic drugs, has also been reported as useful. Hydatidiform mole may precede or be followed by choriocarcinoma, and methotrexate has been used in similar doses for the treatment of hydatidiform mole and chorioadenoma destruens.
Breast Carcinoma Prolonged cyclic combination with cyclophosphamide, methotrexate and fluorouracil has given good results when used as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes.
Methotrexate dosage was 40 mg/m2 intravenously on the first and eighth days. Leukaemia Acute granulocytic leukaemia is rare in children but common in adults and this form of leukaemia responds poorly to chemotherapy. Methotrexate is not generally a drug of choice for induction of remission of lymphoblastic leukaemia.
The most common adverse reactions include ulcerative stomatitis, leukopenia, nausea and abdominal distress. Although very rare, anaphylactic reactions to methotrexate have occurred. Others reported are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.
In general, the incidence and severity of side effects are considered to be dose-related.
Adverse reactions as reported for the various systems are as follows:
Skin: Severe, occasionally fatal, dermatologic reactions including erythema multiforme, Stevens-Johnson syndrome, skin necrosis, epidermal necrolysis. Erythematous rashes, pruritus, urticaria, dermatitis, photosensitivity reactions (frequency uncommon), pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis.
Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration in psoriatic patients and rarely painful erosion of psoriatic plaques have been reported. The recall phenomenon has been reported in both radiation and solar damaged skin.
Skin exfoliation, dermatitis exfoliative (frequency not known).
Blood:
Bone marrow depression, leukopenia, thrombocytopenia, anaemia hypogammaglobulinaemia, haemorrhage from various sites, septicaemia, lymphoproliferative disorders (frequency very rare).
Alimentary System:
Gingivitis, pharyngitis, stomatitis, mucostitis, anorexia, vomiting, diarrhoea, haematemesis, melaena, gastrointestinal ulceration and bleeding, pancreatitis, enteritis, hepatic toxicity resulting in active liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis, or hepatic cirrhosis.
WARNINGS
Methotrexate must be used only by physicians experienced in antimetabolite chemotherapy. Because of the possibility of fatal or severe toxic reactions, the patient should be fully informed by the physician of the risks involved and be under his constant supervision.
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.
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), thoracic pain, 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. 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. 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. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered.
Methotrexate has the potential for serious, sometimes fatal toxicity. The toxic effects may be related in frequency and severity to the dose or frequency of administration but have been seen at all doses. Because the toxic reactions can occur at any time during therapy, the patients have to be observed closely and must be informed of early signs and symptoms of toxicity.
2). Patients with significantly impaired hepatic function Patients with pre-existing blood dyscrasias, such as significant marrow hypoplasia, leukopenia, thrombocytopenia or anaemia. Patients with active infections. Patients with overt or laboratory evidence of immunodeficiency syndrome(s).
6). 6). 1..
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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3 mg/m2 daily, and prednisolone 40-60 mg/m2 daily for 4-6 weeks has been used. After a remission is attained, methotrexate in a maintenance dosage of 20-30 mg/m2 orally or by intramuscular injection has been administered twice weekly.
Twice weekly doses appear to be more effective than daily drug administration. 5 mg/kg has been administered intravenously every 14 days. Meningeal Leukaemia Some patients with leukaemia are subject to leukaemic invasions of the central nervous system and the CSF should be examined in all leukaemia patients.
Passage of methotrexate from blood to the cerebrospinal fluid is minimal and for adequate therapy the drug should be administered intrathecally. Methotrexate may be given in a prophylactic regimen in all cases of lymphocytic leukaemia.
The dose of intrathecal Methotrexate is constant regardless of age or body surface area in patients over the age of 3 years of age, the maximum intrathecal dose should be 12 mg in such patients. Patients under the age of 3 years should be treated in accordance with combination chemotherapy protocols.
The administration is at weekly intervals and is usually repeated until the cell count of cerebrospinal fluid returns to normal. At this point one additional dose is advised. Large doses may cause convulsions and untoward side effects may occur as with any intrathecal injection, and are commonly neurological in character.
Note:
Only the 50 mg/2 ml presentation should be used for the intrathecal route of administration to prevent accidental overdose. Lymphomas In Burkitt's Tumour, stages 1-2, methotrexate has prolonged remissions in some cases. Recommended dosage is 10-25 mg per day orally for 4 to 8 days.
In stage 3, methotrexate is commonly given concomitantly with other antitumour agents. 5 mg/kg daily. Hodgkin's disease responds poorly to methotrexate and to most types of chemotherapy. Mycosis Fungoides Therapy with methotrexate appears to produce clinical remissions in one half of the cases treated.
5 to 10 mg daily by mouth for weeks or months and dosage should be adjusted according to the patient's response and haematological monitoring. Methotrexate has also been given intramuscularly in doses of 50 mg once weekly or 25 mg twice weekly.
4). The health care provider may need to adjust the dose to prevent accumulation of drug. The table below provided recommended starting doses in renally impaired patients; dosing may need further adjustment due to wide intersubject pK variability.
Table 1 a. Dose adjustments for methotrexate doses <100 mg/m2 in patients with renal impairment Creatinine Clearance (ml/min) % of dose to Administer >60 100 30-59 50 <30 Methotrexate must not be administered. Table 1 b. Dose adjustments for methotrexate doses >100 mg/m2 in patients with renal impairment Creatinine Clearance (ml/min) % of dose to Administer >80 100 = ~80 75 = ~60 63 <60 Methotrexate must not be administered.
Psoriasis Chemotherapy Cases of severe uncontrolled psoriasis, unresponsive to conventional therapy, have responded to weekly single, oral, intramuscular or […]
In rare cases the effect of methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon.
Hepatic:
Hepatic toxicity resulting in significant elevations of liver enzymes, acute liver atrophy, necrosis, fatty metamorphosis, hepatitis, periportal fibrosis, or cirrhosis or death may occur, usually following chronic administration.
Urogenital System:
Renal failure, azotaemia, cystitis, haematuria, defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, foetal defects, severe nephropathy. Vaginitis, vaginal ulcers, cystitis, haematuria and nephropathy have also been reported.
4). Acute pulmonary oedema has also been reported after oral and intrathecal use. Pulmonary fibrosis is rare. A syndrome consisting of pleuritic pain and pleural thickening has been reported following high doses.
Frequency Not Known:
Pulmonary alveolar haemorrhage*. *(has been reported for methotrexate used in rheumatologic and related indications).
Central Nervous System:
Headaches, drowsiness, blurred vision, aphasia, cognitive disorder, hemiparesis and convulsions have occurred possibly related to haemorrhage or to complications from intraarterial catheterization. Convulsion, paresis, Guillain- Barre syndrome and increased cerebrospinal fluid pressure have followed intrathecal administration.
Other reactions related to, or attributed to the use of methotrexate such as pneumonitis, metabolic changes, precipitation of diabetes, osteoporotic effects, abnormal changes in tissue cells and even sudden death have been reported.
There have been reports of leukoencephalopathy following intravenous methotrexate in high doses, or low doses following cranial-spinal radiation. Paraesthesia, hypoaesthesia (frequency very rare).
Cardiac disorders:
Pericarditis, pericardial effusion.
Ear disorders:
Tinnitus.
Eye disorders:
Conjunctivitis. g. fatal sepsis) have also been reported in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases, Pneumocystis carinii pneumonia being the most common. Other reported infections include, pneumonia, nocardiosis, histoplasmosis, cryptococcosis, Herpes Zoster, Herpes Simplex, hepatitis and cytomegalovirus infection, including cytomegaloviral pneumonia.
Musculoskeletal and connective tissue disorders:
Arthralgia/myalgia, Osteonecrosis of jaw (secondary to lymphoproliferative disorders) – frequency unknown.
Psychiatric disorders:
Mood altered. g. thrombophlebitis, pulmonary embolism, arterial, cerebral, deep vein or retinal vein thrombosis).
General disorders and administration site conditions:
Oedema, injection site reaction*, injection site necrosis* (frequency not known). *(parenteral only). Adverse reactions following intrathecal methotrexate are generally classified into three groups, acute, subacute, and chronic. The acute form is a chemical arachnoiditis manifested by headache, back or shoulder pain, nuchal rigidity, and fever.
The subacute form may include paresis, usually transient, paraplegia, nerve palsies, and cerebellar dysfunction. The chronic form is a leukoencephalopathy manifested by irritability, confusion, ataxia, spasticity, occasionally convulsions, dementia, somnolence, coma, and rarely, death.
There is evidence that the combined use of cranial radiation and intrathecal methotrexate increases the incidence of leukoencephalopathy. Additional reactions related to or attributed to the use of methotrexate such as osteoporosis, abnormal (usually 'megaloblastic') red cell morphology, precipitation of diabetes, other metabolic changes, and sudden death have been reported.
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search MHRA Yellow Card in the Google Play or Apple App Store.
Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving methotrexate, mostly in combination with other immunosuppressive medication. PML can be fatal and should be considered in the differential diagnosis in immunosuppressed patients with new onset or worsening neurological symptoms.
Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor (PPI) therapy. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities.
In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted.
Deaths have been reported with the use of methotrexate in the treatment of psoriasis. In 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 the diagnosis has been established by biopsy and/or after dermatological consultation.
1. 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 should be withdrawn immediately. Patients should be advised to report all symptoms or signs suggestive of infection.
2. Methotrexate may be hepatotoxic, particularly at high dosage or with prolonged therapy. Liver atrophy, necrosis, cirrhosis, fatty changes, and periportal fibrosis have been reported.
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. 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. 3. Methotrexate has been shown to be […]