Methotrexate

If overdose potentially lethal myelosuppression. The dose regimen for rheumatic disease is 15-25 mg once per week. If you prescribe it daily by accident the patient may die. Advise must seek medical help if any fever, sore throat, bruising, mouth ulcers. Methotrexate toxicity consider folinic acid 15 mg IV OD.

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• Cytotoxic agent and DMARD
• Potentially lethal if taken or prescribed daily or dosed wrongly

Actions

• Structural analogue of folate
• Methotrexate inhibits dihydrofolic acid reductase
• Reduced formation of tetrahydrofolate
• Blocks DNA synthesis needed for repair and cellular replication
• DMARDS mechanism unclear
• Folinic acid reverses the effects of methotrexate

Indications

• Disease modifying agent in Rheumatoid arthritis - takes 4-6 wks for effect
• Cancer chemotherapy e.g. ALL, NHL, Choriocarcinoma
• Burkitt's lymphoma, Mycosis fungoides (cutaneous T cell lymphoma)
• Ectopic pregnancy, Severe Psoriasis

Dose

• Rheumatoid disease: Methotrexate 7.5 mg once/week increasing by 2.5 mg every 6 weeks to the full dose of 15-25 mg once per week. Give on one day only. Folate deficiency occurs. Give folic acid 5 mg day after MTX was given. Reduced dose with renal impairment and elderly.
• Malignant disease (DAILY): Higher doses given under expert guidance. Only used by oncologists. Specialist use only. Regimens differ greatly. See specialist textbooks and pharmacy guidelines.
• Ectopic pregnancy : single-dose regimens methotrexate is given intramuscularly in a dose of 50 mg/m2 or 1 mg/kg. For the average patient, this results in dosages of 75 to 100 mg. Check local guidelines and protocols.

Dose Range (Doses other than weekly for specialist oncology use only)

Interactions

• Acitretin increases methotrexate toxicity
• NSAIDs/Aspirin/probenicid can cause methotrexate toxicity
• Ciclosporin causes methotrexate toxicity

Cautions

• Effusion e.g. ascites and pleural effusions need drained first or may lead to toxicity
• Avoid hepatotoxic drugs, porphyria
• Fertile Women need effective contraception during methotrexate therapy and for another 3 months

Contraindications

• Methotrexate usage is contraindicated if the patient's estimated glomerular filtration rate (eGFR) is lower than 30ml/min.
• Active infection especially shingles, varicella, HSV, Bacterial infections
• Pregnant women, breastfeeding, renal failure, Large pleural effusion
• Liver dysfunction, kidney dysfunction, immunodeficiency, bone marrow dysfunction,
• Alcoholism, alcoholic liver disease or other chronic liver disease
• Immunodeficiency syndromes
• Rheumatological disease and bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anaemia

Side effects

• GI symptoms (nausea, vomiting, anorexia)
• Transient rises in liver transaminases
• Haematological disturbances
• Bone marrow suppression, stomatitis, diarrhoea
• Hypersensitivity pneumonitis in 2-5% (reversible if detected and stopped early)
• Liver toxicity/fibrosis with prolonged exposure - may need a biopsy
• Oral ulceration (give folate 5 mg od),
• Tumour lysis syndrome, hair loss
• Pneumocystis carinii pneumonia, stomatitis, diarrhoea

Toxicity

• Folic acid often given to reduce toxicity (folic acid is usually taken on a 'non-methotrexate' day).
• Methotrexate toxicity consider folinic acid 15 mg IV OD.