Methotrexate

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

Aspirin SmPCs, including those for 100 mg products, contraindicate aspirin during methotrexate treatment at 15 mg a week or more (aspirin 100 mg and 500 mg SmPCs). Below 15 mg a week the interaction still has to be taken into account, especially with impaired kidney function; if the combination is needed, monitor full blood count and kidney function, particularly in the first days (aspirin SmPCs). The methotrexate SmPC for rheumatological use allows NSAIDs and salicylates to continue with low-dose methotrexate only under strict medical supervision; with any kidney impairment, even mild, NSAIDs are not recommended, and while they are taken blood counts and kidney function are checked more often than the usual schedule (methotrexate 2.5 mg SmPC). With high oncological methotrexate doses, NSAIDs are not given before or together with methotrexate (methotrexate 100 mg/ml SmPC). If the combination cannot be avoided, the FDA advises close monitoring for methotrexate adverse reactions (US methotrexate label).

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 can slow renal excretion of methotrexate and increase its blood, gastrointestinal and kidney toxicity (methotrexate SmPCs). For celecoxib itself, no significant effect on methotrexate pharmacokinetics was found at rheumatological doses (celecoxib SmPC). The US celecoxib label (FDA) also states that celecoxib does not change methotrexate pharmacokinetics, but warns that combining NSAIDs with methotrexate may raise the risk of methotrexate toxicity: neutropenia, thrombocytopenia, renal dysfunction.

Symptoms

Mouth ulcers (mucositis), nausea, diarrhoea, hair loss. Blood counts fall: leukocytes, platelets, erythrocytes. Severe cases: fatal pancytopenia, nephrotoxicity.

Management

With high oncological methotrexate doses, NSAIDs are not given before or together with methotrexate (methotrexate 100 mg/ml SmPC). With low rheumatological doses, NSAIDs may continue only under strict medical supervision, and with any kidney impairment, even mild, the combination is not recommended (methotrexate 2.5 mg SmPC). Take care if the NSAID and methotrexate are given within 24 hours of each other, since methotrexate levels can rise (methotrexate 2.5 mg SmPC). While an NSAID is taken, check full blood count and kidney function more often than the usual methotrexate schedule (methotrexate 2.5 mg SmPC). Both celecoxib labels, Spanish and US (FDA), ask for monitoring of methotrexate toxicity, and the US methotrexate label advises close monitoring for methotrexate adverse reactions if the combination cannot be avoided.

Mechanism

Diclofenac, like other NSAIDs, reduces methotrexate renal clearance. With high-dose methotrexate – fatal myelosuppression and nephrotoxicity. With low-dose methotrexate – higher risk of cytopenia and liver injury.

Symptoms

Same as with ibuprofen: mucositis, cytopenia, rising creatinine and transaminases.

Management

Same approach as methotrexate+ibuprofen. If a rheumatoid arthritis patient needs an NSAID, prefer paracetamol or a short ibuprofen course with lab monitoring.

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

With high-dose (oncology) methotrexate, the Spanish label requires avoiding proton pump inhibitors, especially in renal impairment. Withhold esomeprazole for the course and use an H2-receptor antagonist such as famotidine for gastric protection. With low-dose methotrexate (rheumatology, psoriasis) the combination is possible, but the labels warn about methotrexate accumulation, so monitor blood counts, creatinine and signs of toxicity such as mouth ulcers and diarrhoea, with extra care in reduced kidney function.

Mechanism

Ibuprofen reduces methotrexate renal elimination by inhibiting proximal tubular secretion. With high-dose methotrexate (oncology, high-dose psoriasis) concentration rises 2–3 fold causing severe myelosuppression and mucositis. With low-dose weekly methotrexate (rheumatoid arthritis 7.5–25 mg/week) risk is lower but not absent.

Symptoms

Within 7–14 days: mouth ulcers, fever, infections, bruising, gum bleeding. CBC: leukopenia, thrombocytopenia; rising creatinine.

Management

With high-dose methotrexate, contraindicated: stop NSAID 48 h before infusion, resume no sooner than 2–3 days after. With low-dose weekly methotrexate, choose paracetamol as first-line analgesic. If an NSAID is needed, check CBC, creatinine and transaminases every 2 weeks for the first 2 months.

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

Naproxen, like other prostaglandin synthesis inhibitors, reduces methotrexate clearance and may increase its toxicity (naproxen SmPC). With high-dose methotrexate, NSAID co-administration produced high and prolonged methotrexate levels, up to fatal haematological and gastrointestinal toxicity (AEMPS and FDA methotrexate labels). Naproxen has a half-life of 12–17 hours (FDA label), so its effect lasts longer than that of short half-life NSAIDs.

Symptoms

Mucositis, leukopenia, thrombocytopenia, rising creatinine within 1–2 weeks.

Management

With high-dose methotrexate (oncology regimens, e.g. osteosarcoma), do not give naproxen before or during administration; the AEMPS and FDA methotrexate labels state this directly and give no washout interval. With low-dose methotrexate (rheumatology, psoriasis), the combination may be used with caution: monitor full blood count and renal function, especially if the two are taken less than 24 hours apart. With impaired renal function, including mild impairment, the combination is not recommended (methotrexate SmPCs, including EMA).

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

With high-dose (oncology) methotrexate, the Spanish label requires avoiding proton pump inhibitors, especially in renal impairment. Withhold omeprazole for the course and use an H2-receptor antagonist such as famotidine for gastric protection. Ranitidine is not an option: it has been suspended in the EU since 2020. With low-dose methotrexate (rheumatology, psoriasis) the combination is possible, but the labels warn about methotrexate accumulation, so monitor blood counts, creatinine and signs of toxicity such as mouth ulcers and diarrhoea, with extra care in reduced kidney function.

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).