Methotrexate is a medicine used in low weekly doses to treat inflammatory diseases (such as rheumatoid arthritis and psoriasis) and in higher doses to treat some cancers. In low doses it is taken once a week — confusing this with a daily dose is a serious and dangerous mistake.
Also known as: Methotrexate, metotrexato
Leflunomide + methotrexate: increased risk of hepatotoxicity and marrow suppression.
The leflunomide label states that "for patients at high risk for leflunomide-associated hepatotoxicity (e.g., those taking concomitant methotrexate)" or myelosuppression "the recommended leflunomide dosage is 20 mg once daily without a loading dose" and that, if given together, "follow the American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity with ALT, AST, and serum albumin testing". Both drugs are immunomodulators used in rheumatoid arthritis, often in combination, and both have hepatotoxic and myelotoxic potential. Monitor ALT, AST and albumin monthly during the first 6 months, then quarterly; complete blood count with differential monthly; discontinue if ALT > 3× ULN or signs of myelosuppression. Leflunomide should not be started with a loading dose (100 mg × 3 days) when used with methotrexate; start at 20 mg/day from the beginning.
Leflunomide + methotrexate: additive hepatic and bone marrow toxicity in rheumatoid arthritis. Monitor ALT, AST and blood counts; use without leflunomide loading dose.
Additive toxic effects on the liver and bone marrow.
Transaminases and full blood count monthly; renal function.
Jaundice, fever, infections, oral ulcers.
Combination only in specialist settings, with tight monitoring of transaminases and full blood count.
DailyMed (FDA) — approved Leflunomide label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fc044417-cd9a-42f6-8a3d-a14e7c2f81a2 ; approved Methotrexate label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=757d6cef-6696-7a1c-8074-01258aaa8bdd — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
NSAID + methotrexate: reduced renal clearance and increased MTX toxicity.
Methotrexate is eliminated mainly by renal tubular secretion; NSAIDs reduce this excretion (by competition and by reducing renal blood flow) and can raise methotrexate concentrations and the risk of myelosuppression, mucositis, hepatotoxicity and nephrotoxicity. With high-dose methotrexate (chemotherapy) the combination is contraindicated; with low doses (rheumatoid arthritis, psoriasis) it should be used with caution, monitoring blood count, renal function and mucositis, especially in the elderly.
Ibuprofen + methotrexate: the NSAID reduces renal methotrexate clearance, with a risk of myelosuppression and severe toxicity. Avoid with high doses; monitor closely with low doses.
NSAIDs inhibit renal excretion of methotrexate, raising serum concentrations.
Full blood count and renal function; clinical signs of MTX toxicity.
Oral ulcers, marrow suppression, hepatotoxicity.
Avoid NSAIDs in patients on methotrexate; if needed, prefer paracetamol and monitor.
DailyMed (FDA) — approved Methotrexate label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=757d6cef-6696-7a1c-8074-01258aaa8bdd ; approved Ibuprofen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=291602fa-8ebe-4200-bba7-9798c90f8a50 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Antimalarial + antimetabolite: both affect blood count. Additive risk of myelosuppression.
Both can cause myelosuppression. The combination increases the risk of pancytopenia, especially with high-dose methotrexate.
Blood count, signs of infection.
Pancytopenia.
Monitor blood count weekly during concomitant treatment.
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Aspirin + methotrexate: possible increased methotrexate toxicity (renal clearance).
Salicylates (including aspirin at analgesic doses) reduce the renal tubular secretion of methotrexate and displace it from plasma proteins, increasing its free fraction and systemic exposure. QUADRO 2 of Annex 7 lists methotrexate among the drugs whose toxicity is increased by salicylates and NSAIDs. The clinical consequence is myelosuppression (pancytopenia), mucositis, hepatotoxicity and nephrotoxicity, especially with high-dose methotrexate (oncology) or in renal impairment. In rheumatoid arthritis, low stable doses of methotrexate with aspirin at antiplatelet dose require periodic monitoring of blood count and renal function; analgesic doses should be avoided. During high-dose methotrexate regimens, NSAIDs and salicylates should be withheld and alkaline hydration maintained.
Methotrexate + aspirin: salicylates reduce renal excretion and displace methotrexate — risk of myelosuppression and nephrotoxicity; avoid with high-dose methotrexate.
Aspirin (especially at NSAID doses) may reduce methotrexate renal clearance.
Full blood count and renal function on long-term therapy.
Oral ulcers, signs of marrow suppression.
Prefer paracetamol when possible; monitor full blood count if the combination is needed.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (Salicylates)
Methotrexate + diclofenac: NSAIDs reduce renal methotrexate excretion, increasing its toxicity (especially at anticancer doses) (QUADRO 2).
NSAIDs, including diclofenac, inhibit the renal tubular secretion of organic acids and may reduce methotrexate clearance, in addition to reducing renal flow in susceptible patients: both mechanisms increase methotrexate exposure. QUADRO 2 of Annex 7 lists the combination of NSAIDs with methotrexate as carrying an increased risk of myelosuppression and nephrotoxicity. The interaction is more dangerous with high-dose methotrexate, renal impairment, dehydration and in the elderly. In practice, NSAIDs should be avoided during methotrexate therapy; when analgesic relief is needed, paracetamol should be preferred. If the combination is unavoidable, monitor blood count, renal function and signs of mucositis, and ensure adequate hydration.
Methotrexate + diclofenac: NSAIDs reduce methotrexate renal excretion — risk of pancytopenia and renal failure; avoid, especially at high doses.
NSAIDs inhibit prostaglandins and reduce renal methotrexate excretion — possible increased toxicity, especially at anticancer doses (QUADRO 2, NSAIDs: "Methotrexate: possible increased methotrexate toxicity (especially at anticancer doses)").
Monitor blood counts and renal function during the combination.
Pancytopenia, mucositis, renal failure in a patient on methotrexate + diclofenac.
Avoid NSAIDs in patients on methotrexate; if unavoidable, monitor closely.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (NSAIDs)
Fluoroquinolone + methotrexate: possible increased methotrexate toxicity.
Methotrexate is eliminated mainly by renal tubular secretion, and penicillins and, above all, NSAIDs and some antibiotics such as ciprofloxacin can reduce that clearance (by competition in the renal tubule), raising methotrexate concentrations and the risk of myelosuppression, mucositis and nephrotoxicity. The risk is higher with high-dose methotrexate (chemotherapy) — where the combination should be avoided — and with low doses (rheumatoid arthritis) blood count, renal function and mucositis should be monitored, especially in the elderly.
Ciprofloxacin + methotrexate: the antibiotic can reduce renal methotrexate clearance and increase toxicity. Monitor closely.
Ciprofloxacin may reduce methotrexate renal clearance, raising its concentrations.
Full blood count and renal function during antibiotic therapy.
Marrow suppression: fever, oral ulcers, infections.
Use with caution and monitor full blood count and renal function.
DailyMed (FDA) — approved Methotrexate label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=757d6cef-6696-7a1c-8074-01258aaa8bdd ; approved Ciprofloxacin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c527d138-e32c-418f-9573-a3d8a796279f — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Antifolate + folate antagonist: co-trimoxazole potentiates methotrexate toxicity.
The co-trimoxazole label recommends avoiding concomitant use with methotrexate: sulfonamides can displace methotrexate from plasma protein binding and compete with renal methotrexate transport, raising free methotrexate concentrations; additionally, trimethoprim is an antifolate (dihydrofolate reductase inhibitor) that adds its effect to that of methotrexate, and the methotrexate label lists sulfonamides among the drugs to avoid. The risk of myelosuppression, mucositis and haematological toxicity is particularly relevant with high-dose methotrexate (chemotherapy); even with low doses (rheumatoid arthritis), avoid or, if unavoidable, closely monitor the blood count, renal function and mucositis.
Co-trimoxazole + methotrexate: avoid the combination — additive antifolate effect, protein binding displacement and renal competition with a risk of myelosuppression.
Trimethoprim inhibits dihydrofolate reductase and reduces methotrexate renal clearance, risking severe marrow suppression.
Full blood count and renal function; reassess methotrexate dose.
Fever, infections, oral ulcers, anaemia, leucopenia, thrombocytopenia.
Avoid the combination when possible; if unavoidable, monitor full blood count and renal function frequently.
DailyMed (FDA) — approved Methotrexate label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=757d6cef-6696-7a1c-8074-01258aaa8bdd ; approved Co-trimoxazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08500fcb-dbec-4ac2-91c3-189d27907ec0 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Penicillin G benzathine may increase plasma methotrexate concentrations, with an increased risk of toxicity (myelosuppression, hepatotoxicity).
The methotrexate label identifies penicillins among the drugs that can increase plasma methotrexate concentrations: penicillins inhibit the renal tubular secretion of methotrexate, reducing its clearance and raising levels, with risk of toxicity (myelosuppression, mucositis, hepatotoxicity, nephrotoxicity) — especially with high-dose methotrexate or in patients with impaired renal function and dehydration. In patients receiving methotrexate and benzathine benzylpenicillin, monitor renal function and signs of methotrexate toxicity, and consider measuring serum levels when clinically indicated.
Benzylpenicillin + methotrexate: penicillins reduce renal methotrexate clearance — risk of toxicity.
Oral or intravenous penicillins are listed in the methotrexate label among drugs that may increase methotrexate exposure (possible reduced renal tubular secretion of methotrexate and protein-binding displacement).
Blood count (myelosuppression), liver and renal function, signs of mucositis, stomatitis or bleeding.
Haematological or hepatic toxicity, pancytopenia, severe mucositis.
Monitor closely for methotrexate toxicity when coadministration cannot be avoided; consider methotrexate dose adjustment.
DailyMed/FDA (NIH/NLM) — approved Methotrexate label (section 7.1 Effects of Other Drugs on Methotrexate): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=04a95db9-a124-4b97-bd71-1c37a6b3b0c8 ; approved Bicillin L-A label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=012d46f1-d0a0-4676-a879-cd320297ab16
Acitretin + Methotrexate is CONTRAINDICATED: increased risk of hepatitis with the combination.
The acitretin label is explicit: an increased risk of hepatitis has been reported with the combined use of methotrexate and etretinate (the precursor of acitretin) and, consequently, the combination of methotrexate with acitretin is contraindicated. Both drugs are potentially hepatotoxic and the risk of liver injury is additive. In severe psoriasis, if methotrexate is an option, acitretin should not be used together; consider monotherapy or an alternative (e.g., phototherapy, biologics) and monitor liver function after any accidental exposure.
Acitretin + methotrexate: CONTRAINDICATED — increased risk of hepatitis with the combination.
An increased risk of hepatitis has been reported with the combined use of methotrexate and etretinate (a precursor of acitretin); consequently, the combination of methotrexate with acitretin is contraindicated.
Monitor liver function if there is accidental exposure.
Jaundice, elevated transaminases or signs of hepatitis.
Do not use the combination. Choose an alternative psoriasis therapy.
DailyMed/FDA (NIH/NLM) — approved Acitretin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a6546625-acb8-460e-b34e-f795bfb3680a ; approved Methotrexate label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=04a95db9-a124-4b97-bd71-1c37a6b3b0c8
Methotrexate + amoxicillin: penicillins may reduce renal excretion of methotrexate and increase its toxicity.
The Prontuário documents for methotrexate "penicillins (reduced excretion)" among the relevant interactions. Penicillins compete with methotrexate for renal tubular secretion, reducing its elimination and raising plasma levels, with a risk of toxicity (myelosuppression, mucositis, hepatotoxicity). The combination is clinically relevant in patients on high-dose methotrexate or with borderline renal function. If amoxicillin therapy is needed, monitor the blood count and signs of mucositis, consider methotrexate level monitoring in high-dose regimens and reinforce hydration. Any fever, neutropenia or oral ulcers should prompt immediate evaluation.
Methotrexate + amoxicillin: monitor methotrexate toxicity — penicillins reduce its renal excretion.
The Prontuário documents for methotrexate: "Interactions: NSAIDs (reduced excretion); penicillins (reduced excretion); phenytoin (increased toxicity); ciclosporin (increased toxicity); probenecid (reduced excretion)". Penicillins compete with methotrexate for renal tubular secretion, reducing its elimination and raising plasma levels.
Blood count, renal function and signs of mucositis/oral ulcers during the combination.
Fever, neutropenia, mucositis, haematuria or sudden renal function decline during the combination.
Monitor for signs of methotrexate toxicity (myelosuppression, mucositis, hepatotoxicity) during penicillin antibiotic therapy; consider methotrexate level monitoring at high doses.
DailyMed/FDA (NIH/NLM) — approved Methotrexate label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=04a95db9-a124-4b97-bd71-1c37a6b3b0c8 ; approved Amoxicillin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57e56202-950b-10f6-e063-6394a90a4912 ; Prontuário Terapêutico do INFARMED (11th ed., 2012) — Methotrexate, 16.1.3
Methotrexate + phenytoin: risk of increased methotrexate toxicity (and possibly reduced phenytoin levels).
The Prontuário documents for methotrexate "phenytoin (increased toxicity)". Phenytoin is highly protein-bound and the combination involves protein displacement and metabolic changes that may increase methotrexate toxicity; conversely, methotrexate may alter phenytoin levels. The combination is relevant in oncology patients with concomitant epilepsy. Monitor signs of methotrexate toxicity (myelosuppression, mucositis) and, if applicable, serum phenytoin levels; any ataxia, nystagmus or neurological symptoms should prompt evaluation. Consider an alternative anticonvulsant when seizure control allows.
Methotrexate + phenytoin: monitor methotrexate toxicity and phenytoin levels — risk of increased toxicity.
The Prontuário documents "phenytoin (increased toxicity)" for methotrexate. Phenytoin is highly protein-bound and the interaction involves displacement and metabolic changes — the methotrexate label lists phenytoin among drugs requiring caution.
Blood count and clinical monitoring of adverse effects during the combination.
Fever, neutropenia, mucositis or signs of phenytoin intoxication (nystagmus, ataxia).
Monitor for signs of methotrexate toxicity (myelosuppression, mucositis) and, if applicable, phenytoin levels.
DailyMed/FDA (NIH/NLM) — approved Methotrexate label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=04a95db9-a124-4b97-bd71-1c37a6b3b0c8 ; approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3580e6a8-f7c3-44a0-a1eb-2a84ae589d21 ; Prontuário Terapêutico do INFARMED (11th ed., 2012) — Methotrexate, 16.1.3
Injectable NSAID + antimetabolite: methotrexate renal clearance reduced. Risk of toxicity.
Ketorolac reduces renal blood flow and tubular secretion of methotrexate, increasing serum levels and prolonging half-life.
Blood count, methotrexate levels.
Pancytopenia, mucositis.
Avoid combination during high-dose methotrexate treatment. If necessary, monitor blood count and methotrexate levels.
DailyMed/FDA — approved Ketorolac label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0749f61d-12e6-4280-8f41-bd4df81e7ae6
NSAID + antimetabolite: methotrexate renal clearance reduced. Risk of toxicity (myelosuppression, mucositis).
Indomethacin reduces renal blood flow and tubular secretion of methotrexate, which is primarily excreted renally (80-90% unchanged). Reduced clearance can increase methotrexate levels by 20-50%, depending on dose and renal function. High-dose methotrexate (>100 mg/m²) is especially dangerous with NSAIDs — the risk of pancytopenia, severe mucositis, and hepatotoxicity increases significantly. At low doses (10-25 mg/week for arthritis), the risk is lower but remains relevant. Monitor blood count (leukocytes, platelets) and hepatic enzymes.
Potent NSAID + antimetabolite: methotrexate renal clearance reduced. Risk of toxicity (myelosuppression, mucositis, hepatotoxicity).
Indomethacin reduces renal blood flow and tubular secretion of methotrexate, increasing serum levels. Risk of pancytopenia and mucositis.
Blood count, methotrexate levels, signs of mucositis.
Pancytopenia, severe mucositis, neutrophils <500/mm³.
Avoid NSAIDs during high-dose methotrexate. If necessary, monitor blood count weekly and methotrexate levels.
DailyMed/FDA — approved Indomethacin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2997707-1541-4f5d-8c8d-70b0a13be8b2
NSAID + antimetabolite: methotrexate renal clearance may be reduced.
Nimesulide may reduce tubular secretion of methotrexate. The effect is less than with non-selective NSAIDs, but clinically relevant at high methotrexate doses.
Blood count, methotrexate levels.
Pancytopenia, mucositis.
Avoid NSAIDs during high-dose methotrexate. If necessary, monitor blood count.
Prontuário Terapêutico; EMC-EMC Portugal — Nimesulide
SSRI + antimetabolite: SSRI may reduce renal clearance of methotrexate.
Some SSRIs may reduce tubular secretion of methotrexate, increasing levels. The effect is less than with NSAIDs, but clinically relevant at high methotrexate doses (>15 mg/week). Monitor blood count if concomitant treatment. At low methotrexate doses (7.5-15 mg/week for rheumatoid arthritis), the risk is lower.
SSRI + antimetabolite: SSRI may reduce renal clearance of methotrexate. Risk of pancytopenia.
Some SSRIs may reduce tubular secretion of methotrexate. The effect is less than with NSAIDs.
Blood count.
Pancytopenia.
Monitor blood count if concomitant treatment.
DailyMed/FDA
Taking with food reduces methotrexate-related nausea.
Take with food to improve GI tolerance.
EMC-UK (MHRA) — approved Methotrexate SmPC: https://www.medicines.org.uk/emc/product/511/smpc
Alcohol potentiates methotrexate hepatotoxicity.
Avoid alcohol during treatment (additive liver risk).
EMC-UK (MHRA) — approved Methotrexate SmPC: https://www.medicines.org.uk/emc/product/511/smpc
Alcohol adds hepatotoxicity to that of methotrexate.
Advise alcohol abstinence during treatment.
EMC-UK (MHRA) — approved Methotrexate SmPC: https://www.medicines.org.uk/emc/product/511/smpc
Methotrexate is renally excreted; severe renal impairment raises toxicity.
Contraindicated in severe renal impairment; adjust dose in moderate impairment.
EMC-UK (MHRA) — approved Methotrexate SmPC: https://www.medicines.org.uk/emc/product/511/smpc
Methotrexate is hepatotoxic and may worsen active liver disease.
Contraindicated in active liver disease; monitor transaminases on therapy.
EMC-UK (MHRA) — approved Methotrexate SmPC: https://www.medicines.org.uk/emc/product/511/smpc
Methotrexate is teratogenic and abortifacient; contraindicated in pregnancy and planned conception.
Contraindicated; use effective contraception during and up to 3-6 months after treatment (men: 3 months).
Contraindicated during breastfeeding.
Effective contraception mandatory during and up to 3-6 months after therapy.
EMC-UK (MHRA) — approved Methotrexate SmPC: https://www.medicines.org.uk/emc/product/511/smpc
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Folate antagonist with antiproliferative and immunomodulatory effects: inhibits dihydrofolate reductase, blocking thymidylate and purine synthesis, essential for DNA replication and cell proliferation. At low weekly doses (inflammatory diseases) the anti-inflammatory effect is also related to increased extracellular adenosine.
Methotrexate binds to and competitively inhibits dihydrofolate reductase (DHFR), depleting intracellular reduced folate and blocking thymidylate and purine synthesis. Leucovorin (folinic acid) bypasses this block — hence its use as rescue after high doses.
At doses ≤30 mg/m2, mean bioavailability is ~60%, with peak plasma concentrations 0.75–6 hours after oral administration; food delays absorption and reduces the peak. Methotrexate is ~50% protein bound and does not penetrate the blood-brain barrier at recommended concentrations. Enterohepatic recirculation may occur.
Methotrexate is partially metabolised by intestinal flora after oral administration and, mainly, metabolised in the liver and intracellularly to active polyglutamated forms (which can be converted back to methotrexate). It also undergoes minor metabolism to active 7-hydroxymethotrexate. Excretion is predominantly renal (glomerular filtration and active tubular secretion); biliary excretion accounts for ≤10%.
The elimination half-life is ~3–10 hours. Small amounts of polyglutamates may remain in tissues for extended periods — the retention and prolonged action of these active metabolites vary among cells, tissues and tumours. The half-life increases with the severity of renal impairment.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
