Antimetabolites, folic acid analogues
ATC code: L01BA01 (Methotrexate)
Brand names
Trexall, Otrexup, Rasuvo
Competitive dihydrofolate reductase inhibitor. At high doses (oncology), suppresses DNA synthesis and cell proliferation. At low weekly doses (rheumatic disease), the anti-inflammatory effect predominates via adenosine accumulation and suppressed T-cell activation. Low-dose weekly therapy mandates concurrent folic acid 5 mg weekly the day after methotrexate — reduces hepatotoxicity, nausea, and stomatitis without losing efficacy.
First line
In psoriasis and psoriatic arthritis, methotrexate is first-line systemic therapy for moderate-to-severe disease per 2020 and GRAPPA 2021. In juvenile idiopathic arthritis — first-line disease-modifying therapy. Used in protocols for ANCA-associated vasculitis and giant cell arteritis.
Psoriasis and psoriatic arthritis, juvenile idiopathic arthritis, vasculitides.
First line
Per 2023 and 2021, methotrexate is the first-line anchor drug for rheumatoid arthritis. Start 7.5–15 mg weekly orally; with inadequate response or oral intolerance — subcutaneous 15–25 mg weekly. Concomitant folic acid 5 mg weekly the day after methotrexate is mandatory. Effect develops over 6–12 weeks.
Second line
In Crohn disease, methotrexate is used as a thiopurine alternative when those agents are intolerated or ineffective per 2021 and 2020. Evidence is weaker in ulcerative colitis, where methotrexate is rarely used. Dose 25 mg subcutaneously weekly.
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
Not recommended
Use of methotrexate in viral URI or cold is not described in any international source. The drug is an immunosuppressant with a serious side-effect profile; use outside rheumatologic, dermatologic, gastrointestinal, or oncologic indications is unacceptable.
17 pairs found. Sorted from critical to minor.
Mechanism
Co-trimoxazole contains trimethoprim, a dihydrofolate reductase inhibitor. Methotrexate blocks the same enzyme system. Co-administration intensifies the antifolate effect and suppresses haematopoiesis. Fatal pancytopenia and severe mucositis have been reported, even at low rheumatological methotrexate doses.
Symptoms
Stomatitis, mouth ulcers, nausea. Then – falling leukocyte and platelet counts: increased infection susceptibility and bleeding. Severe cases progress to fatal pancytopenia. Symptoms appear after 1–2 weeks of combined dosing.
Management
The combination is not recommended. For urinary tract infections in a patient on methotrexate, use nitrofurantoin or fosfomycin. For Pneumocystis infection where co-trimoxazole cannot be replaced, hold methotrexate for the antibiotic course and check full blood count every 3–5 days. Folic acid supplementation is mandatory.
Mechanism
Aspirin suppresses tubular secretion of methotrexate and displaces it from albumin binding. Methotrexate plasma levels rise – particularly dangerous at oncologic doses.
Symptoms
Mouth ulcers (mucositis), nausea, diarrhoea, hair loss. Blood counts fall: leukocytes, platelets, erythrocytes. Severe cases include fatal pancytopenia, nephrotoxicity, and hepatotoxicity.
Management
At oncologic methotrexate doses, the combination is not prescribed. At low rheumatologic doses (5–25 mg/week), cardioprotective aspirin (75–100 mg/day) is acceptable when renal function is preserved, with full blood count and creatinine every 1–3 months.
Mechanism
Amoxicillin and other penicillins compete with methotrexate for renal tubular secretion. Methotrexate clearance falls and plasma levels rise – risk of myelosuppression and toxicity at oncologic doses.
Symptoms
Mouth ulcers (mucositis), nausea, diarrhoea, hair loss. Blood counts fall: leukocytes, platelets, erythrocytes. Severe cases: fatal pancytopenia, nephrotoxicity.
Management
At oncologic methotrexate doses, avoid amoxicillin. Alternative antibiotics: a cephalosporin or macrolide (azithromycin, doxycycline). At low rheumatologic doses, a short amoxicillin course is acceptable with blood count monitoring.
Mechanism
NSAIDs reduce renal methotrexate clearance (both selective and non-selective COX inhibitors).
Symptoms
Mouth ulcers (mucositis), nausea, diarrhoea, hair loss. Blood counts fall: leukocytes, platelets, erythrocytes. Severe cases: fatal pancytopenia, nephrotoxicity.
Management
At oncologic methotrexate doses, the combination is not prescribed. At low rheumatologic doses, celecoxib is acceptable with full blood count and creatinine monitoring every 1–3 months.
Mechanism
Diclofenac suppresses renal methotrexate excretion via prostaglandin-dependent blood flow inhibition and competition for tubular secretion. Methotrexate plasma levels rise – particularly dangerous at oncologic doses.
Symptoms
Mouth ulcers (mucositis), nausea, diarrhoea, hair loss. Blood counts fall: leukocytes, platelets, erythrocytes. Severe cases include fatal pancytopenia, nephrotoxicity, and hepatotoxicity.
Management
At oncologic methotrexate doses, the combination is not prescribed. At low rheumatologic doses, short diclofenac courses are acceptable with full blood count and creatinine monitoring. For chronic analgesia: paracetamol or celecoxib.
Mechanism
Proton pump inhibitors block the renal BCRP transporter and reduce methotrexate clearance. At high oncologic doses, risk of delayed elimination and severe toxicity.
Symptoms
Mouth ulcers (mucositis), nausea, diarrhoea, hair loss. Blood counts fall: leukocytes, platelets, erythrocytes. Severe cases: fatal pancytopenia, nephrotoxicity.
Management
At oncologic methotrexate doses, stop esomeprazole 5 days before and resume 5 days after dosing. Alternative: famotidine (H2-blocker, no BCRP effect). At low rheumatologic doses, esomeprazole is acceptable with blood count monitoring.
Mechanism
Ibuprofen (NSAID) suppresses renal methotrexate excretion via prostaglandin-dependent renal blood flow inhibition and competition for tubular secretion. Methotrexate plasma levels rise – particularly dangerous at oncologic doses.
Symptoms
Mouth ulcers (mucositis), nausea, diarrhoea, hair loss. Blood counts fall: leukocytes, platelets, erythrocytes. Severe cases include fatal pancytopenia, nephrotoxicity, and hepatotoxicity.
Management
At oncologic methotrexate doses, the combination is not prescribed. At low rheumatologic doses, short ibuprofen courses are acceptable with full blood count and creatinine monitoring. For chronic analgesia: paracetamol or celecoxib (minimal risk).
Mechanism
Contrast-induced nephropathy lowers renal methotrexate clearance. At high oncologic methotrexate doses, plasma levels rise and severe toxicity risk (pancytopenia, mucositis, nephrotoxicity) increases.
Symptoms
Stomatitis, diarrhoea, falling leukocyte, platelet, and erythrocyte counts. Severe cases include fatal pancytopenia and acute kidney injury. Symptoms appear 3–7 days after contrast.
Management
At oncologic methotrexate doses, postpone contrast studies for 2–4 weeks after methotrexate administration. If contrast is urgent, ensure adequate hydration and check full blood count and creatinine daily. Add folinic acid rescue.
Mechanism
Ketorolac reduces renal methotrexate clearance and suppresses tubular secretion. At high oncologic methotrexate doses: risk of severe toxicity (pancytopenia, nephrotoxicity, mucositis).
Symptoms
Mouth ulcers (mucositis), nausea, diarrhoea, hair loss. Blood counts fall: leukocytes, platelets, erythrocytes. Severe cases: fatal pancytopenia, nephrotoxicity.
Management
At oncologic methotrexate doses, the combination is not prescribed. At low rheumatologic doses, avoid ketorolac; use paracetamol or a short opioid course for analgesia. Ketorolac courses never exceed 5 days.
Mechanism
NSAIDs reduce renal methotrexate clearance. At high oncologic doses: myelosuppression and mucositis. At low rheumatologic doses, risk is smaller but monitoring is needed.
Symptoms
Stomatitis, diarrhoea, falling leukocyte, platelet, and erythrocyte counts. Severe cases: fatal pancytopenia, nephrotoxicity.
Management
At oncologic methotrexate doses, the combination is not prescribed. At low rheumatologic doses, meloxicam is acceptable for a short course with blood count and creatinine monitoring every 1–3 months.
Mechanism
NSAIDs reduce renal methotrexate clearance via renal blood flow blockade and can displace methotrexate from plasma protein binding. Fatal cases have been reported at high oncologic methotrexate doses.
Symptoms
Mouth ulcers (mucositis), nausea, diarrhoea, hair loss. Blood counts fall: leukocytes, platelets, erythrocytes. Severe cases: fatal pancytopenia, nephrotoxicity.
Management
At oncologic methotrexate doses, the combination is not prescribed. At low rheumatologic doses, a short naproxen course is acceptable with blood count and creatinine monitoring. For chronic analgesia: paracetamol or celecoxib.
Mechanism
Omeprazole blocks the renal BCRP transporter and reduces methotrexate clearance. At oncologic methotrexate doses, plasma levels rise 2- to 3-fold, with reported severe nephrotoxicity and pancytopenia.
Symptoms
Mouth ulcers (mucositis), nausea, diarrhoea, hair loss. Blood counts fall: leukocytes, platelets, erythrocytes. Severe cases include fatal pancytopenia, nephrotoxicity, and hepatotoxicity.
Management
At oncologic methotrexate doses, the combination is not prescribed. During methotrexate cycles, replace omeprazole with ranitidine or famotidine (H2-blockers, no BCRP effect). At low rheumatologic doses, risk is minimal; omeprazole is acceptable with full blood count monitoring.
Mechanism
Proton pump inhibitors block the renal BCRP transporter, reducing methotrexate clearance. At high oncologic doses: risk of severe delayed toxicity.
Symptoms
Mouth ulcers (mucositis), nausea, diarrhoea, hair loss. Blood counts fall: leukocytes, platelets, erythrocytes. Severe cases: fatal pancytopenia, nephrotoxicity.
Management
At oncologic methotrexate doses, stop pantoprazole 5 days before and resume 5 days after dosing. Alternative: famotidine (H2-blocker, no BCRP effect). At low rheumatologic doses, pantoprazole is acceptable.
Mechanism
Dual immunosuppression plus additive nephrotoxicity. The combination is used in rheumatoid arthritis patients on methotrexate when tacrolimus is added (e.g., in ANCA vasculitis), requiring careful monitoring.
Symptoms
Stomatitis, diarrhoea, falling leukocyte, platelet, and erythrocyte counts. Severe cases: fatal pancytopenia, nephrotoxicity.
Management
The combination is possible in rheumatic disease with careful monitoring. Check full blood count, creatinine, and liver enzymes every 2 weeks for the first 3 months, then monthly. Keep tacrolimus trough (C0) at the lower end of target range.
Mechanism
No direct pharmacokinetic interaction. Cases of enhanced hepatotoxicity have been reported with long-term co-use, since both drugs can cause steatohepatitis and liver fibrosis.
Symptoms
Fatigue, nausea, jaundice, elevated liver enzymes. Symptoms develop with long-term therapy (over 6 months).
Management
On the combination, check ALT, AST, and alkaline phosphatase every 3 months. If enzymes rise 2–3-fold above the upper limit, repeat at 2 weeks; if persistently elevated, consider temporary methotrexate withdrawal. In rheumatoid arthritis, alternative: leflunomide (if no liver fibrosis).
Mechanism
Atorvastatin blocks OATP1B1 – the hepatic methotrexate uptake route. Methotrexate plasma levels may rise. The effect is clinically significant at high oncologic methotrexate doses.
Symptoms
Stomatitis, diarrhoea, falling leukocyte and platelet counts. In patients with borderline renal function: severe toxicity risk.
Management
At low rheumatological methotrexate doses (5–25 mg/week), the combination is acceptable without adjustment. At high oncologic doses, temporarily withhold atorvastatin for 24–48 hours after methotrexate administration.
Mechanism
Antibiotics may affect methotrexate gut absorption. Low clinical significance at rheumatological methotrexate doses (5–25 mg weekly).
Symptoms
Mostly no changes. At high oncologic methotrexate doses: risk of rising levels with toxicity symptoms (stomatitis, diarrhoea, falling leukocyte count).
Management
At low rheumatological methotrexate doses, the combination is acceptable without adjustment. At high oncologic doses: avoid azithromycin; alternative antibiotics (a cephalosporin, nitrofurantoin for UTI).
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Boxed warning
FDA boxed warning: methotrexate is a teratogen and abortifacient, contraindicated in pregnancy (category X). Inadvertent daily dosing (instead of weekly) has caused fatal overdoses. Hepatotoxicity, myelosuppression, severe pulmonary complications, severe cutaneous reactions, and tumors (including lymphomas) occur with long-term therapy.
FDA categories were retired in 2015 (historically X). The drug is teratogenic and abortifacient. Use in pregnancy is absolutely contraindicated. Women of reproductive age require reliable contraception during therapy and for at least 6 months after discontinuation. Men: at least 3 months before planned conception. Inadvertent pregnancy on therapy — immediate discontinuation and genetic counseling.
Contraindicated during breastfeeding — the drug transfers into milk.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
Methotrexate is evaluated for the following indications with varying evidence strength: Rheumatoid arthritis (evidence tier A), Autoimmune conditions (evidence tier A), Inflammatory bowel disease (IBD) (evidence tier B). See the full indication matrix with dosing and citations above on this page.
Common side effects of Methotrexate (≥ 1 in 100): Nausea, post-dose discomfort, Stomatitis, oral ulcers, Fatigue, Transaminase elevation, Alopecia (mild, reversible), Decreased appetite. See the Safety section for uncommon and serious reactions.
FDA category X. FDA categories were retired in 2015 (historically X). The drug is teratogenic and abortifacient. Use in pregnancy is absolutely contraindicated. Women of reproductive age require reliable contraception during therapy and for at least 6 months after discontinuation. Men: at least 3 months before planned conception. Inadvertent pregnancy on therapy — immediate discontinuation and genetic counseling.
Contraindicated during breastfeeding — the drug transfers into milk.
Methotrexate is contraindicated in: Pregnancy and breastfeeding; Severe hepatic impairment; Severe renal impairment (eGFR below 30); Active severe infections; Active tuberculosis. Full list in the Safety section.
FDA boxed warning: methotrexate is a teratogen and abortifacient, contraindicated in pregnancy (category X). Inadvertent daily dosing (instead of weekly) has caused fatal overdoses. Hepatotoxicity, myelosuppression, severe pulmonary complications, severe cutaneous reactions, and tumors (including lymphomas) occur with long-term therapy.
rheumatic doses are 100–500 fold lower than oncology doses. The side-effect profile at these doses is fundamentally different — manageable and largely preventable.
moderate occasional intake (1–2 drinks weekly) is acceptable; regular heavy drinking raises hepatotoxicity risk and is contraindicated.
folic acid 5 mg is taken once weekly on the day after methotrexate — this regimen reduces adverse effects without compromising therapeutic effect per EULAR.