Oskela
Get started

Drug Reference

methotrexate

antimetabolite immunosuppressant· Brands: Trexall, Rheumatrex, Maxtrex, Metoject, Otrexup, RasuvoIMIVPOSC

Mechanism of action
Methotrexate inhibits dihydrofolate reductase, an enzyme that reduces dihydrofolate to tetrahydrofolate, a cofactor required for the synthesis of thymidylate and purines. This action disrupts DNA and RNA synthesis, preferentially affecting rapidly dividing cells. In inflammatory conditions, methotrexate also promotes adenosine release, which contributes to its anti-inflammatory and immunomodulatory effects.
Pharmacokinetics
After oral administration, methotrexate is absorbed variably, and food can affect bioavailability. Low doses are largely metabolised intracellularly to polyglutamates, which are retained and prolong the drug's activity. The drug is distributed widely and is excreted primarily by the kidneys, so renal impairment reduces clearance. Plasma half-life is short, but intracellular polyglutamates can persist for weeks.
Indications & dosing

Rheumatoid arthritis

Use once weekly; folic acid 5 mg once weekly may reduce side effects.

  • adult · PO: 7.5–15 mg weekly · Use once weekly; folic acid 5 mg once weekly may reduce side effects.

Psoriasis

Use once weekly; monitor liver function and blood count.

  • adult · PO: 10–25 mg weekly · Use once weekly; monitor liver function and blood count.

Psoriatic arthritis

Once weekly dosing; avoid in pregnancy.

  • adult · PO: 7.5–20 mg weekly · Once weekly dosing; avoid in pregnancy.

Crohn's diseaseoff-label

Off-label; give as subcutaneous injection.

  • adult · SC: 15–25 mg weekly · Off-label; give as subcutaneous injection.

Ectopic pregnancy

Single dose; follow beta-hCG levels.

  • adult · IM: 50 mg/m2 single dose · Single dose; follow beta-hCG levels.
Contraindications & precautions
  • Pregnancy · Teratogenic; effective contraception required during and for at least 3 months after treatment.
  • Breastfeeding · Methotrexate is excreted in breast milk; risk of infant toxicity.
  • Severe renal impairment · Risk of drug accumulation and toxicity. Consider alternative with severe renal failure.
  • Severe hepatic impairment or chronic liver disease · Risk of worsening hepatotoxicity.
  • Hypersensitivity to methotrexate · Cross-reactivity with other disease-modifying antirheumatic drugs.
  • Active infection or bone marrow suppression · Use with caution; monitor blood counts closely.
  • Monitor full blood count, liver and renal function regularly (at baseline and periodically during treatment).
  • Administer folic acid (or folinic acid) supplementation to reduce the risk of toxicity (in non-oncologic use).
  • Ensure adequate hydration and consider urine alkalinisation when using high-dose methotrexate to prevent nephrotoxicity.
  • Advise effective contraception during and for at least 3 months after treatment; confirm non-pregnancy before initiation (in women of childbearing potential).
  • Avoid concomitant use of nephrotoxic or hepatotoxic drugs (e.g., NSAIDs, trimethoprim) as they can increase methotrexate toxicity.
Adverse effects
  • Nausea and vomiting
  • Stomatitis and mucositisserious
  • Bone marrow suppression (leukopenia, thrombocytopenia, anaemia)serious
  • Hepatotoxicity (elevated transaminases, hepatic fibrosis)serious
  • Pulmonary toxicity (interstitial pneumonitis)serious
  • Renal toxicity (renal impairment, tubular necrosis)serious
  • Alopecia
Interactions
  • amoxicillinmajorAvoid concurrent use if possible. If unavoidable, use with caution and monitor serum methotrexate concentrations, full blood count, and renal function. Consider reducing the methotrexate dose and providing appropriate rescue with folinic acid. An alternative antibiotic should be considered in high-dose methotrexate regimens.
  • ibuprofenmajorAvoid the concomitant use of methotrexate and ibuprofen, especially in patients with renal impairment, elderly patients, or those receiving high-dose methotrexate. If no alternative anti-inflammatory or analgesic agent is available, monitor closely: check renal function, complete blood counts, and methotrexate levels frequently. Consider dose reduction of methotrexate and ensure adequate hydration and urinary alkalinisation where appropriate.
  • omeprazolemajorAvoid concurrent use of omeprazole with high-dose methotrexate. If co-administration is unavoidable, monitor methotrexate plasma levels, renal function, and full blood counts closely. Consider alternative acid-suppressive therapy such as an H2 receptor antagonist if required.
  • fluconazolemajorAvoid concurrent use if possible. If unavoidable, reduce the methotrexate dose and monitor closely. Monitor full blood count, liver and renal function, and methotrexate plasma levels, with dose adjustment as needed.
  • co-trimoxazolecontraindicatedCo-prescription is contraindicated. Avoid concurrent use. If absolutely necessary, use alternative antibiotics with no antifolate activity. Monitor full blood count and methotrexate levels frequently if co-administration is unavoidable.
  • diclofenacmajorAvoid co-prescription if possible. If necessary, use with extreme caution: monitor renal function, blood counts, and methotrexate levels frequently; consider a lower methotrexate dose and ensure adequate hydration and alkalinisation.
  • aspirinmajorAvoid concurrent use if possible. If combination is necessary, use a lower methotrexate dose, monitor plasma methotrexate concentrations, renal function, and full blood count closely, and adjust therapy accordingly.
  • naproxenmajorAvoid concurrent use of methotrexate and naproxen, particularly in patients with renal impairment or those receiving high-dose methotrexate. If co-prescription is unavoidable, use the lowest effective doses and monitor closely. Monitor full blood count, renal function, and liver function at baseline and at regular intervals during therapy. Consider measuring serum methotrexate levels where available. Administer methotrexate with folic acid supplementation to reduce some toxicities. Advise patients to report signs of toxicity such as oral ulcers, fever, or easy bruising.
  • probenecidmajorAvoid co-prescription. If treatment with both drugs is essential, do not use high-dose methotrexate. For low-dose methotrexate, consider a substantial dose reduction, or alternative uricosuric or anti-inflammatory agents. Monitor plasma methotrexate concentrations, full blood count, serum creatinine, and liver function tests frequently. Provide supportive care such as hydration and leucovorin rescue as appropriate.
  • trimethoprimmajorAvoid co-prescription where possible, especially with high-dose methotrexate. If combined use is essential, closely monitor full blood counts, renal function and serum methotrexate levels. Consider prophylactic folic acid, ensure adequate hydration, and adjust doses accordingly. Consult specialist advice for each individual case.
Renal & hepatic adjustment
  • eGFR 60–300: No dose adjustment needed.
  • eGFR 30–59: Reduce dose by 50% or consider alternative; monitor closely.
  • eGFR 0–29: Avoid; contraindicated in severe renal impairment. (avoid)
  • Hepatic impairment (mild): Use with caution; monitor liver function tests regularly.
  • Hepatic impairment (moderate): Consider dose reduction; avoid if evidence of significant liver disease.
  • Hepatic impairment (severe): Avoid; contraindicated in severe hepatic impairment. (avoid)
Monitoring, pregnancy & toxicity
  • Full blood count · Baseline, then weekly for first 2 weeks, then every 2-4 weeks
  • Liver function tests (ALT, AST, bilirubin) · Baseline, then every 1-2 months
  • Serum creatinine/eGFR · Baseline, then every 1-3 months
  • Pregnancy test (for women of childbearing age) · Before start, then before each dose
  • Pregnancy: Contraindicated in pregnancy. Teratogenic and abortifacient. Women must use effective contraception during treatment and for at least 6 months after stopping. Men should use contraception for at least 3 months after stopping.
  • Toxicity: Myelosuppression (pancytopenia) · Stop methotrexate; give folinic acid (leucovorin) rescue; supportive care (e.g., G-CSF if neutropenic, antibiotics if febrile).
  • Toxicity: Mucositis/stomatitis · Stop methotrexate; give folinic acid; analgesia, mouth care, ensure hydration.
  • Toxicity: Hepatotoxicity · Stop methotrexate; monitor LFTs; give folinic acid; consider liver biopsy if persistent.
  • Toxicity: Pulmonary toxicity (pneumonitis) · Stop methotrexate; supportive care; consider corticosteroids.
Antidotes & reversal
  • Folinic acid (leucovorin rescue) · Leucovorin rescue started as soon as possible; glucarpidase for very high levels.
Clinical notes
Low-dose weekly methotrexate is used as a disease-modifying antirheumatic drug in rheumatoid arthritis, psoriatic arthritis, and severe psoriasis. High-dose regimens are used in oncology. Folic acid supplementation is commonly co-prescribed to reduce gastrointestinal and bone marrow toxicity. Monitor full blood count, liver function, and renal function. Contraindicated in pregnancy, breastfeeding, and significant hepatic or renal impairment. Pulmonary toxicity is a rare but serious adverse effect.

Log in to read the full methotrexate monograph

A free account unlocks the complete drug reference, the interaction checker, prescription practice and every other learning tool.

Log inCreate a free account

BNF; local formulary