Formulary
Methotrexate: Indications, Dosing, Side Effects and Interactions
Methotrexate inhibits the enzyme dihydrofolate reductase, essential for the synthesis of purines and pyrimidines.
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Methotrexate: Indications, Dosing, Side Effects and Interactions
Methotrexate inhibits the enzyme dihydrofolate reductase, essential for the synthesis of purines and pyrimidines.
Drug action
Methotrexate inhibits the enzyme dihydrofolate reductase, essential for the synthesis of purines and pyrimidines.
Indications and dose
**Mild to moderate Crohn's disease refractory or intolerant to thiopurines (under expert supervision)**
- **Adult** (By Subcutaneous Injection): Initially 25 mg once weekly until remission induced; maintenance 15 mg once weekly.
**Severe Crohn's disease (under expert supervision)**
- **Adult** (By Intramuscular Injection): Initially 25 mg once weekly until remission induced; maintenance 15 mg once weekly.
**Maintenance of remission of severe Crohn's disease (under expert supervision)**
- **Adult** (By Mouth): 10-25 mg once weekly.
**Moderate to severe active rheumatoid arthritis (under expert supervision)**
- **Adult** (By Mouth): 7.5 mg once weekly, adjusted according to response; maximum 20 mg per week.
**Severe active rheumatoid arthritis (under expert supervision)**
- **Adult** (By Intramuscular Injection, Or By Subcutaneous Injection): Initially 7.5 mg once weekly, then increased in steps of 2.5 mg once weekly, adjusted according to response; maximum 25 mg per week.
**Neoplastic diseases (specialist use only)**
- **Adult** (By Mouth, Or By Intravenous Injection, Or By Intravenous Infusion, Or By Intra-Arterial Infusion, Or By Intramuscular Injection, Or By Intrathecal Injection): Specialist indication - access specialist resources for dosing information.
**Severe psoriasis unresponsive to conventional therapy (under expert supervision)**
- **Adult** (By Mouth, Or By Intramuscular Injection, Or By Intravenous Injection, Or By Subcutaneous Injection): Initially 2.5-10 mg once weekly, then increased in steps of 2.5-5 mg, adjusted according to response, dose to be adjusted at intervals of at least 1 week; usual dose 7.5-15 mg once weekly, stop treatment if inadequate response after 3 months at the optimum dose; maximum 30 mg per week.
**Severe Crohn's disease (under expert supervision) for methotrexate**
- **Child 7-17 years** (By subcutaneous injection, or by intramuscular injection): 15 mg/m2 once weekly (max. per dose 25 mg).
**Maintenance of remission of severe Crohn's disease (under expert supervision) for methotrexate**
- **Child 7-17 years** (By mouth, or by subcutaneous injection, or by intramuscular injection): 15 mg/m2 once weekly (max. per dose 25 mg), dose reduced according to response to lowest effective dose.
**Juvenile idiopathic arthritis (under expert supervision), Juvenile dermatomyositis (under expert supervision), Vasculitis (under expert supervision), Uveitis (under expert supervision), Systemic lupus erythematosus (under expert supervision), Localised scleroderma (under expert supervision), Sarcoidosis (under expert supervision) for methotrexate**
- **Child** (By mouth, or by subcutaneous injection, or by intramuscular injection): Initially 10-15 mg/m2 once weekly, then increased if necessary up to 25 mg/m2 once weekly.
**Maintenance and remission of acute lymphoblastic leukaemia, lymphoblastic lymphoma (specialist use only) for methotrexate**
- **Child** (By mouth): Specialist indication - access specialist resources for dosing information.
**Treatment of early stage Burkitt's lymphoma, non-Hodgkin's lymphoma, osteogenic sarcoma, some CNS tumours including infant brain tumours, acute lymphoblastic leukaemia (specialist use only) for methotrexate**
- **Child** (By intravenous injection, or by intravenous infusion): Specialist indication - access specialist resources for dosing information.
**Meningeal leukaemia, treatment and prevention of CNS involvement of leukaemia (specialist use only) for methotrexate**
- **Child** (By intrathecal injection): Specialist indication - access specialist resources for dosing information.
**Severe psoriasis unresponsive to conventional therapy (under expert supervision) for methotrexate**
- **Child 2-17 years** (By mouth): Initially 200 micrograms/kg once weekly (max. per dose 10 mg), then increased if necessary to 400 micrograms/kg once weekly (max. per dose 25 mg), adjusted according to response, stop treatment if inadequate response after 3 months at the optimum dose.
Cautions
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.
Contraindications
Active infection; ascites; immunodeficiency syndromes; significant pleural effusion
Side effects
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.
Interactions
**Severe interactions:**
- Administration of additional haematotoxic medicinal products increases the likelihood of severe haematotoxic adverse reactions to methotrexate.
- The use of nitrous oxide potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression and stomatitis and in case of...
- Combination with valproate Case reports describe a significant decrease in valproate serum levels and the occurrence of clinical symptoms such as epileptic seizures within a few hours of...
**Other interactions (33):**
- The risk of an interaction between NSAIDs and methotrexate should be considered in patients with a low methotrexate dose, particularly in the case of impaired kidney function.
- Caution should be exercised if NSAIDs and methotrexate are administered within 24 hours, since in this case methotrexate plasma levels can rise and toxicity be increased as a result.
- Animal studies showed that the administration of NSAIDs including salicylic acid resulted in reduced tubular methotrexate secretion and accordingly potentiated its toxic effects.
- Treatment of rheumatoid arthritis with such medicinal products can be continued during therapy with low-dose methotrexate, but only under close medical supervision.
- Patients taking potentially hepatotoxic medicinal products during treatment with methotrexate (e.g.
- The consumption of alcohol should be avoided during treatment with methotrexate (see section 4.4).
Pregnancy
Avoid (teratogenic; fertility may be reduced during therapy but this may be reversible).
Breast feeding
Discontinue breast-feeding-present in milk.
Hepatic impairment
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
Risk of nephrotoxicity at high doses. Use with caution; avoid in severe impairment. M Dose adjustments Reduce dose (consult product literature). M
Medicinal forms
Solution,Tablet,Suspension,Solution,Solution,Solution
Clinical governance
**Author:** MedNext Clinical Team. **Clinical reviewer:** Dr Shameer Deen, MBBS, MS, MRCS. **Sources:** BNF, Indian Pharmacopoeia, CIMS India. **Correction:** Report errors at support@mednext.academy.
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