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Methotrexate inhibits the enzyme dihydrofolate reductase, essential for the synthesis of purines and pyrimidines.
Indications and dose
For methotrexate
Mild to moderate Crohn's disease refractory or intolerant to thiopurines (under expert supervision)
By subcutaneous injection
- Adult
- Initially 25 mg once weekly until remission induced; maintenance 15 mg once weekly.
Severe Crohn's disease (under expert supervision)
By intramuscular injection
- Adult
- Initially 25 mg once weekly until remission induced; maintenance 15 mg once weekly.
Maintenance of remission of severe Crohn's disease (under expert supervision)
By mouth
- Adult
- 10–25 mg once weekly.
Moderate to severe active rheumatoid arthritis (under expert supervision)
By mouth
- Adult
- 7.5 mg once weekly, dose to be adjusted according to response up to maximum 20 mg per week.
Severe active rheumatoid arthritis (under expert supervision)
By intramuscular injection, or by subcutaneous injection
- Adult
- Initially 7.5 mg once weekly, dose increased in steps of 2.5 mg once weekly, dose to be adjusted according to response up to maximum 25 mg per week.
Neoplastic diseases (specialist use only)
By mouth, or by intravenous injection, or by intravenous infusion, or by intra-arterial infusion, or by intramuscular injection, or by intrathecal injection
- Adult
- Specialist indication – access specialist resources for dosing information.
Severe psoriasis unresponsive to conventional therapy (under expert supervision)
By mouth, or by intramuscular injection, or by intravenous injection, or by subcutaneous injection
- Adult
- Initially 2.5–10 mg once weekly, dose increased in steps of 2.5–5 mg, dose to be adjusted according to response at intervals of at least 1 week up to maximum 30 mg per week, usual dose 7.5–15 mg once weekly, stop treatment if inadequate response after 3 months at the optimum dose.
Unlicensed use
For methotrexate
Not licensed for use in severe Crohn's disease.
Important safety information
For methotrexate
NHS Never Event: Overdose of methotrexate for non-cancer treatment (January 2018)
Patients given methotrexate, by any route, for non-cancer treatment should not be given more than their intended weekly dose.
Weekly Dosing
Note that the dose is a weekly dose. To avoid error with low-dose methotrexate, it is recommended that:
the patient or their carer is carefully advised of the dose and frequency and the reason for taking methotrexate and any other prescribed medication (e.g. folic acid);
only one strength of methotrexate tablet (usually 2.5 mg) is prescribed and dispensed;
the prescription and the dispensing label clearly show the dose and frequency of methotrexate administration;
the patient or their carer is warned to report immediately the onset of any feature of blood disorders (e.g. sore throat, bruising, and mouth ulcers), liver toxicity (e.g. nausea, vomiting, abdominal discomfort, and dark urine), and respiratory effects (e.g. shortness of breath).
MHRA/CHM advice: Methotrexate once-weekly for autoimmune diseases: new measures to reduce risk of fatal overdose due to inadvertent daily instead of weekly dosing (September 2020)
With oral use:
Methotrexate should be taken once a week in autoimmune conditions and, less commonly, in some cancer therapy regimens. A European review highlighted continued reports of inadvertent overdose due to more frequent dosing (including daily administration), which has resulted in some fatalities. Subsequently, new measures have been implemented by the MHRA.
Prescribers are advised to:
ensure patients can understand and comply with once-weekly dosing before prescribing methotrexate, decide with the patient which day of the week they will take their dose, and note this down in full on the prescription;
consider the patient's overall polypharmacy burden when deciding which formulation to prescribe, especially in those with a high pill burden;
inform patients and carers of the potentially fatal risk of accidental overdose if methotrexate is taken more frequently than once a week, and reaffirm that it should not be taken daily;
advise patients and carers to seek immediate medical attention if overdose is suspected.
The MHRA further advises dispensers to remind patients of the once-weekly dosing and the risks of potentially fatal overdose if they take more than directed. Where possible, the day of the week for dosing should be written in full in the space provided on the outer packaging. Patients should be encouraged to write the day of the week for dosing in their patient alert card and carry it with them.
MHRA/CHM advice: Methotrexate: advise patients to take precautions in the sun to avoid photosensitivity reactions (August 2023)
Photosensitivity reactions, including phototoxicity, are known side-effects of methotrexate that may occur with low- and high-dose treatment. These reactions are distinct from radiation recall reactions, and can appear as severe sunburn (e.g. rashes with papules or blistering, and sometimes swelling); rarely, photosensitivity reactions have contributed to deaths from secondary infections.
Healthcare professionals are reminded to inform patients and their carers of the risk and signs of photosensitivity reactions during methotrexate treatment, and advise them to:
avoid exposure to UV light (including intense sunlight, especially between 11 a.m. and 3 p.m., sunlamps, and sunbeds);
use a sunscreen with a high sun protection factor (SPF) and wear protective clothing during sun exposure;
speak to a healthcare professional if they have concerns about a skin reaction.
Contra-indications
For methotrexate
Active infection; ascites; immunodeficiency syndromes; significant pleural effusion
Cautions
For methotrexate
Dehydration (increased risk of toxicity); diarrhoea; extreme caution in blood disorders (avoid if severe); peptic ulceration (avoid in active disease); photosensitivity; risk of accumulation in pleural effusion or ascites—drain before treatment; ulcerative colitis; ulcerative stomatitis
Cautions, further information
Blood count
Bone marrow suppression can occur abruptly; factors likely to increase toxicity include advanced age, renal impairment, and concomitant use with another anti-folate drug (e.g. trimethoprim). Manufacturer advises a clinically significant drop in white cell count or platelet count calls for immediate withdrawal of methotrexate and introduction of supportive therapy.
Gastro-intestinal toxicity
Manufacturer advises withdraw treatment if stomatitis or diarrhoea develops—may be first sign of gastro-intestinal toxicity.
Photosensitivity
Psoriasis lesions may be aggravated by UV radiation—skin ulceration has been reported.
Radiation recall reaction has been reported in both radiation- and sun-damaged skin.
Liver toxicity
Liver cirrhosis reported. Manufacturer advises treatment should not be started or should be discontinued if any abnormality of liver function or liver biopsy is present or develops during therapy. Abnormalities can return to normal within 2 weeks after which treatment may be recommenced if judged appropriate. Persistent increases in liver transaminases may necessitate dose reduction or discontinuation.
Pulmonary toxicity
Pulmonary toxicity may be a special problem in rheumatoid arthritis. Manufacturer advises patients to seek medical attention if dyspnoea, cough or fever develops; monitor for symptoms at each visit—discontinue if pneumonitis suspected.
Interactions
Side-effects
For methotrexate
General side-effects:
Uncommon
Seizure
Specific side-effects:
Common or very common
With oral use
Anaemia; appetite decreased; diarrhoea; drowsiness; fatigue; gastrointestinal discomfort; headache; increased risk of infection; interstitial lung disease; leucopenia; nausea; oral disorders; respiratory disorders; skin reactions; throat ulcer; thrombocytopenia; vomiting
With parenteral use
Anaemia; appetite decreased; diarrhoea; drowsiness; fatigue; gastrointestinal discomfort; headache; interstitial lung disease; leucopenia; nausea; oral disorders; respiratory disorders; skin reactions; throat ulcer; thrombocytopenia; vomiting
Uncommon
With oral use
Agranulocytosis; alopecia; arthralgia; bone marrow disorders; chills; confusion; cystitis; depression; diabetes mellitus; dysuria; fever; gastrointestinal disorders; haemorrhage; healing impaired; hepatic disorders; myalgia; neoplasms; nephropathy; osteoporosis; photosensitivity reaction; pulmonary fibrosis; rheumatoid arthritis aggravated; severe cutaneous adverse reactions (SCARs); vasculitis; vertigo; vulvovaginal disorders
With parenteral use
Agranulocytosis; alopecia; arthralgia; bone marrow disorders; confusion; cystitis; depression; diabetes mellitus; drug toxicity; dysuria; gastrointestinal disorders; haemorrhage; healing impaired; hepatic disorders; increased risk of infection; local reaction; myalgia; neoplasms; osteoporosis; photosensitivity reaction; pulmonary fibrosis; rheumatoid arthritis aggravated; severe cutaneous adverse reactions (SCARs); vasculitis; vertigo; vulvovaginal disorders
Rare or very rare
With oral use
Asthma; azotaemia; brain oedema; cognitive impairment; conjunctivitis; cough; dyspnoea; embolism and thrombosis; eosinophilia; gynaecomastia; hypotension; immune deficiency; infertility; insomnia; lymphadenopathy; meningism; meningitis aseptic; menstrual cycle irregularities; mood altered; muscle weakness; nail discolouration; neutropenia; pain; pancreatitis; paresis; pericardial disorders; pericarditis; proteinuria; psychosis; radiation injuries; renal impairment; retinopathy; sensation abnormal; sepsis; sexual dysfunction; speech impairment; sperm abnormalities; stress fracture; taste altered; telangiectasia; tinnitus; vision disorders
With parenteral use
Apnoea; asthma-like conditions; azotaemia; conjunctivitis; cough; dyspnoea; embolism and thrombosis; eosinophilia; fever; gynaecomastia; hypotension; immune deficiency; infertility; insomnia; lymphadenopathy; meningism; meningitis aseptic; menstrual cycle irregularities; mood altered; muscle weakness; nail discolouration; neutropenia; pain; pericardial disorders; pericarditis; proteinuria; reactivation of infection; renal impairment; retinopathy; sensation abnormal; sepsis; sexual dysfunction; sperm abnormalities; stress fracture; taste altered; telangiectasia; vision disorders
Frequency not known
With intrathecal use
Arachnoiditis; cerebrospinal fluid pressure increased; Guillain-Barre syndrome; leukoencephalopathy; paresis; pulmonary oedema
With oral use
Chest pain; death; defective oogenesis; dizziness; electrolyte imbalance; encephalopathy; mucositis; neurotoxicity; oedema; progressive multifocal leukoencephalopathy (PML); pulmonary oedema; reactivation of infection; skin ulcer
With parenteral use
Aphasia; chills; cognitive disorder; defective oogenesis; dizziness; hemiparesis; injection site necrosis; leukoencephalopathy; metabolic change; mucositis; necrosis; nephropathy; oedema; pancreatitis; progressive multifocal leukoencephalopathy (PML); radiation injuries; skin ulcer; sudden death; tinnitus
Side-effects, further information
Give folic acid to reduce side-effects. Folic acid decreases mucosal and gastrointestinal side-effects of methotrexate and may prevent hepatotoxicity; there is no evidence of a reduction in haematological side-effects.
Withdraw treatment if ulcerative stomatitis develops—may be first sign of gastro-intestinal toxicity.
Treatment with folinic acid (as calcium folinate) may be required in acute toxicity.
Conception and contraception
For methotrexate
Females of childbearing potential should use effective contraception during treatment and for at least 6 months after last treatment; male patients should use effective contraception during treatment and for at least 3 months after last treatment if their partner is of childbearing potential.
Pregnancy
For methotrexate
Avoid (teratogenic; fertility may be reduced during therapy but this may be reversible).
Breast feeding
For methotrexate
Discontinue breast-feeding—present in milk.
Hepatic impairment
For methotrexate
When used for malignancy, avoid in severe hepatic impairment—consult local treatment protocol for details.
Avoid with hepatic impairment in non-malignant conditions—dose-related toxicity.
Renal impairment
For methotrexate
Risk of nephrotoxicity at high doses.
Use with caution; avoid in severe impairment.
Dose adjustments
Reduce dose (consult product literature).
Pre-treatment screening
For methotrexate
Exclude pregnancy before treatment.
Patients should have full blood count and renal and liver function tests before starting treatment.
Monitoring requirements
For methotrexate
Monitoring of patient parameters
In view of reports of blood dyscrasias (including fatalities) and liver cirrhosis with low-dose methotrexate patients should:
have full blood count and renal and liver function tests repeated every 1–2 weeks until therapy stabilised, thereafter patients should be monitored every 2–3 months.
be advised to report all symptoms and signs suggestive of infection, especially sore throat
Local protocols for frequency of monitoring may vary.
Treatment with folinic acid (as calcium folinate) may be required in acute toxicity.
Prescribing and dispensing information
For methotrexate
Folinic acid following methotrexate administration helps to prevent methotrexate-induced mucositis and myelosuppression.
The licensed routes of administration for parenteral preparations vary—further information can be found in the product literature for the individual preparations.
Risk minimisation materials documents are available for healthcare professionals.
Patient and carer advice
For methotrexate
Patients and their carers should be warned to report immediately the onset of any feature of blood disorders (e.g. sore throat, bruising, and mouth ulcers), liver toxicity (e.g. nausea, vomiting, abdominal discomfort and dark urine), and respiratory effects (e.g. shortness of breath).
Patients and their carers should be advised to avoid exposure to UV light (including intense sunlight, sunlamps, and sunbeds)—see Important safety information.
Patients should be advised to avoid self-medication with over-the-counter aspirin or ibuprofen.
Patients should be counselled on the dose, treatment booklet, and the use of NSAIDs.
With oral use:
A patient alert card should be provided to patients on once-weekly dosing—see also Important safety information.
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