Methotrexate

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Dosing and administration^[3]

Once weekly (oral or subcutaneous) for rheumatoid arthritis and psoriasis. The weekly, not daily, schedule is a critical safety point: inadvertent daily dosing has caused fatal toxicity, so it should be emphasized to the patient and pharmacist. Oral bioavailability is reduced by food, particularly milk products. Folic or folinic acid supplementation reduces gastrointestinal, mucosal, hepatic, and hematologic toxicity and is routinely co-prescribed.

Onset. Therapeutic response usually begins within 3 to 6 weeks; further improvement may continue for 12 weeks or more.

Renal adjustment. Adjust the starting dose to renal function (contraindicated in severe renal impairment and end stage renal disease): creatinine clearance above 80 mL/min, full dose; 80 mL/min, about 75%; 60 mL/min, about 63%; 50 mL/min, about 56%; below 50 mL/min, use alternative therapy. Further adjustment may be needed given wide pharmacokinetic variability, and renal impairment prolongs methotrexate elimination.

Hepatic. Use with caution in pre-existing liver damage or impaired hepatic function; dose adjustment may be needed and liver function should be monitored regularly. Contraindicated in the setting of alcoholism, alcoholic liver disease, or other chronic liver disease in rheumatoid arthritis or psoriasis, and not recommended in active or chronic hepatitis B or C infection.

Starting doses, renal adjustment, monitoring, contraindications, and interactions are from the Health Canada product monograph. The 25 mg per week maximum used for rheumatoid arthritis reflects the clinic's protocol and standard rheumatology practice, which exceeds the monograph's 20 mg per week label; it is not drawn from the monograph.

Monitoring

• Baseline: complete blood count with differential and platelets, liver enzymes, renal function tests, and a chest X-ray.
• Hematologic: at least monthly, and more frequently when starting or changing the dose.
• Liver enzymes: at baseline, then every 1 to 2 months.
• Renal function: every 1 to 2 months.
• Respiratory: pulmonary function tests if methotrexate-induced lung disease (interstitial pneumonitis) is suspected.

Contraindications

• Pregnancy in rheumatoid arthritis or psoriasis, and women of childbearing potential until pregnancy is excluded; breast-feeding.
• Alcoholism, alcoholic liver disease, or other chronic liver disease (rheumatoid arthritis or psoriasis).
• Overt or laboratory evidence of immunodeficiency; pre-existing blood dyscrasias (marrow hypoplasia, leucopenia, thrombocytopenia, or significant anemia).
• Severe renal impairment, including end stage renal disease with or without dialysis.
• Concurrent nitrous oxide anesthesia.
• Hypersensitivity to methotrexate or any component of the formulation.

Key interactions

• NSAIDs and salicylates: use with caution at the low weekly doses used in rheumatoid arthritis (they can raise methotrexate levels); avoid with high-dose methotrexate.
• Proton pump inhibitors (omeprazole, esomeprazole, pantoprazole): can raise and prolong methotrexate levels, mainly at high dose; avoid the combination, especially in renal impairment.
• Nitrous oxide anesthesia: contraindicated (potentiates antifolate toxicity).
• Other hepatotoxic or antifolate agents (leflunomide, azathioprine, sulfasalazine, retinoids, trimethoprim-sulfamethoxazole): monitor for additive hepatotoxicity or marrow suppression.
• Probenecid, penicillins, and sulfonamides: reduce renal clearance of methotrexate; monitor closely.
• Folic acid: routinely co-prescribed to reduce methotrexate toxicity (given on a different day).

Clinical notes

Common side effects

Nausea, stomatitis, and fatigue are common and often mitigated by folate or switching to subcutaneous administration; cytopenias and transaminitis occur less commonly. Not sourced on this draft.

Tests and monitoring

Baseline complete blood count, liver transaminases, and serum creatinine before starting, with hepatitis B and C screening where risk factors are present. On treatment, check CBC, transaminases, and creatinine every 2 to 4 weeks for the first 3 months, every 8 to 12 weeks from 3 to 6 months, and every 12 weeks beyond 6 months, testing more often after a dose increase. This is the ACR conventional-DMARD monitoring schedule, defined for rheumatoid arthritis. Limit alcohol given the risk of hepatotoxicity.^{[1, 2]}

Alcohol

PRACTICE POSITION, not a guideline-derived threshold: Dr. Mahendira advises no more than one standard drink per week while on methotrexate. Practice varies between rheumatologists and this is recorded as her position rather than a general standard. Canada's Guidance on Alcohol and Health (CCSA, 2023) is population guidance and is not methotrexate-specific. It replaced the 2011 low-risk drinking guidelines and is framed as a continuum of risk rather than a limit: 2 standard drinks or fewer per week is the level at which alcohol-related consequences are largely avoided; 3 to 6 per week increases the risk of several cancers; 7 or more per week significantly increases cardiovascular risk; and no more than 2 on any occasion. No known safe amount in pregnancy or when trying to conceive, and none is safest when breastfeeding. A Canadian standard drink is 17.05 mL or 13.45 g of ethanol. The Health Canada product monograph contraindicates methotrexate in alcoholism, alcoholic liver disease and other chronic liver disease. That is narrower than a blanket instruction to abstain, and the distinction is worth making explicitly when counselling. QUANTIFIED HEPATOTOXICITY DATA (Humphreys 2017, primary read in full). UK primary-care cohort, 11,839 RA patients starting methotrexate, 530 first episodes of transaminitis (ALT or AST at or above three times the upper limit of normal) in 47,090 person-years, crude rate 11.26 per 1000 person-years. Against non-drinkers, age and gender adjusted hazard ratios by weekly UK units were 1.03 (0.82 to 1.28) for 1 to 7, 1.01 (0.73 to 1.40) for 8 to 14, 1.35 (0.85 to 2.14) for 15 to 21, and 1.85 (1.17 to 2.93) for more than 21. Per unit consumed, 1.01 (1.00 to 1.02). The posterior probability of a clinically important increase in risk, defined a priori as 50% or more, was 0.93% below 14 units per week, 33% at 15 to 21, and 81% above 21. CONVERSION MATTERS HERE. A UK unit is 8 g of ethanol and a Canadian standard drink is 13.45 g, so 14 UK units is roughly 8.3 Canadian standard drinks and 21 units roughly 12.5. The reassurance in that study therefore sits well above both the Canadian guidance figures and the practice position above. Quoting its threshold in Canadian drinks without converting would overstate it by about two thirds. Limitations the authors state: alcohol was self-reported and recorded once, so change over time was not captured; inclusion required at least six transaminase measurements a year, which may have excluded heavier drinkers who attend less; few events occurred in the high-consumption groups; methotrexate dose was not modelled, and if lower doses are prescribed to heavier drinkers the risk at high intake may be underestimated; transaminitis may not capture fibrosis progressing without enzyme rises; and the cohort was rheumatoid arthritis only, not generalisable to psoriasis, where background liver disease is more common. The practice variation is longstanding and documented in that paper: ACR guidance from 1994 advised abstinence with only occasional exceptions, while BSR guidance from 2008 advised staying well within UK national recommendations without further specification.^{[4, 5, 3]}

Important cautions

Contraindicated in pregnancy (teratogen); reproductive-health guidance is covered in the pregnancy record. Caution with significant infection, renal impairment, and live vaccines; peri-operative considerations apply. To confirm from primary sources.

References

1. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59(6):762-784. doi:10.1002/art.23721 https://doi.org/10.1002/art.23721
2. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res. 2016;68(1):1-25. doi:10.1002/acr.22783 (published simultaneously in Arthritis & Rheumatology) https://doi.org/10.1002/acr.22783
3. ACH-METHOTREXATE (methotrexate tablets 2.5 mg) Product Monograph. Accord Healthcare Inc. Health Canada authorized product monograph, revised 15 July 2025. Submission Control Number 295682. https://pdf.hres.ca/dpd_pm/00081040.PDF
4. Paradis C, Butt P, Shield K, et al, and the Low-Risk Alcohol Drinking Guidelines Scientific Expert Panels. Canada's Guidance on Alcohol and Health: Final Report. Canadian Centre on Substance Use and Addiction; January 2023. https://www.ccsa.ca/canadas-guidance-alcohol-and-health-final-report
5. Humphreys JH, Warner A, Costello R, Lunt M, Verstappen SMM, Dixon WG. Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate. Ann Rheum Dis. 2017;76(9):1509-1514. doi:10.1136/annrheumdis-2016-210629 https://doi.org/10.1136/annrheumdis-2016-210629