Methotrexate
Rheumatrex, Trexall, Otrexup, Rasuvo, Reditrex, Xatmep, Jylamvo
Indications for Methotrexate
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Rheumatoid arthritis — severe, active | Adults | Monotherapy or combination with biologics | FDA Approved |
| Polyarticular juvenile idiopathic arthritis (pJIA) | Pediatric | Monotherapy or combination | FDA Approved |
| Severe psoriasis — recalcitrant, disabling | Adults | Monotherapy | FDA Approved |
| Acute lymphoblastic leukemia (ALL) — maintenance | Adults & pediatric | Combination chemotherapy | FDA Approved |
| Meningeal leukemia — prophylaxis & treatment | Adults & pediatric | Intrathecal | FDA Approved |
| Non-Hodgkin lymphoma | Adults | Combination chemotherapy | FDA Approved |
| Osteosarcoma — adjuvant, high-dose | Adults & pediatric | Combination with leucovorin rescue | FDA Approved |
| Breast cancer | Adults | Combination chemotherapy | FDA Approved |
| Head and neck carcinoma — epidermoid | Adults | Combination chemotherapy | FDA Approved |
| Mycosis fungoides (cutaneous T-cell lymphoma) | Adults | Monotherapy or combination | FDA Approved |
Methotrexate is one of the most widely prescribed disease-modifying agents in rheumatology and is the recommended first-line DMARD for rheumatoid arthritis by the American College of Rheumatology (ACR 2021). In oncology, dosing ranges from moderate oral doses for maintenance ALL to high-dose IV regimens exceeding 12 g/m² for osteosarcoma, always paired with leucovorin rescue. The drug’s versatility across autoimmune and neoplastic indications stems from its dual mechanism of folate antagonism and immunomodulation at differing dose ranges.
Ectopic pregnancy — single-dose or multi-dose IM regimens for unruptured ectopic pregnancy (ACOG, evidence quality: High).
Psoriatic arthritis — used as a first-line conventional DMARD despite limited RCT data (GRAPPA/EULAR, evidence quality: Moderate).
Inflammatory myopathies (dermatomyositis/polymyositis) — steroid-sparing agent (evidence quality: Moderate).
Systemic lupus erythematosus — for skin and joint manifestations refractory to hydroxychloroquine (evidence quality: Moderate).
Crohn disease — induction and maintenance in patients intolerant of thiopurines (evidence quality: Moderate).
Sarcoidosis — steroid-sparing for pulmonary and extrapulmonary disease (evidence quality: Low).
Graft-versus-host disease prophylaxis — in combination with calcineurin inhibitors (evidence quality: High).
Dosing for Methotrexate
Adult — Autoimmune & Dermatologic Indications
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| RA — newly diagnosed, DMARD-naive | 7.5 mg PO once weekly | 15–25 mg once weekly | 25 mg/week (oral); 30 mg/week (SC) | Escalate by 5 mg/month to optimal response Co-prescribe folic acid 1 mg daily (skip MTX day) or 5 mg weekly |
| RA — suboptimal oral response, switching to SC | Same mg dose SC weekly | 15–25 mg SC weekly | 30 mg/week SC | SC route has higher bioavailability at doses >15 mg Consider before adding a biologic |
| RA — combination with biologic DMARD | 10–15 mg once weekly | 10–25 mg once weekly | 25 mg/week | Often maintained at lower doses for immunogenicity reduction Improves biologic efficacy and reduces anti-drug antibodies |
| Psoriasis — severe plaque, recalcitrant | 10–15 mg PO once weekly | 15–25 mg once weekly | 25 mg/week | Reduce to lowest effective dose once controlled Consider test dose of 5–10 mg first week to screen for idiosyncratic toxicity |
| Ectopic pregnancy — single-dose protocol | 50 mg/m² IM single dose | Repeat at Day 7 if beta-hCG decline <15% | Up to 2 additional doses | Measure beta-hCG Days 4 and 7 Off-label but well-established (ACOG) |
Pediatric Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Polyarticular JIA | 10 mg/m² PO/SC once weekly | 10–15 mg/m² once weekly | 20 mg/m²/week (or 25 mg/week absolute) | Adjust based on response and tolerability SC preferred if GI intolerance or doses >15 mg/m² |
| ALL — maintenance therapy | 20 mg/m² PO once weekly | Adjust to maintain target ANC | Per protocol | Part of multi-agent regimen Monitor ANC; hold if ANC <500 |
| Meningeal leukemia — intrathecal | Age-based: 6 mg (<1 y), 8 mg (1 y), 10 mg (2 y), 12 mg (≥3 y) | Per protocol schedule | 12 mg IT (max 15 mg in adults) | Use preservative-free formulation ONLY Reconstitute with preservative-free saline to 1 mg/mL |
Oncology — High-Dose Regimens
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Osteosarcoma — adjuvant | 12 g/m² IV over 4 hours | Per protocol cycle schedule | 20 g per dose (absolute) | Mandatory leucovorin rescue beginning 24 h post-infusion Requires aggressive hydration, urine alkalinization, and serum MTX level monitoring |
| CNS lymphoma — high-dose IV | 3–8 g/m² IV over 2–4 hours | q14 days per protocol | 8 g/m² | Leucovorin rescue required Achieves therapeutic CSF concentrations despite blood-brain barrier |
Renal Impairment
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| CrCl 30–60 mL/min — low-dose autoimmune use | Reduce dose by 50% | Guided by tolerance and CBC | 15 mg/week | More frequent CBC monitoring Renal excretion is the primary elimination route |
| CrCl <30 mL/min | Avoid methotrexate — high risk of severe myelosuppression and mucositis due to delayed elimination | |||
Fatal medication errors have occurred when methotrexate prescribed as a weekly dose for autoimmune indications was mistakenly taken daily. Always specify the day of the week on prescriptions, counsel patients explicitly that methotrexate for RA or psoriasis is taken once weekly — not daily — and document the designated dosing day.
Pharmacology of Methotrexate
Mechanism of Action
Methotrexate enters cells via the reduced folate carrier (SLC19A1) and undergoes intracellular polyglutamation by folylpolyglutamate synthase. Both the parent compound and its polyglutamated forms potently inhibit dihydrofolate reductase (DHFR), blocking the reduction of dihydrofolate to tetrahydrofolate — a cofactor essential for thymidylate and purine nucleotide synthesis. This disrupts DNA synthesis and repair, producing cytotoxicity in rapidly proliferating cells. At the lower doses used in autoimmune disease, the dominant therapeutic mechanism shifts toward immunomodulation: methotrexate promotes extracellular adenosine release by inhibiting AICAR transformylase, which suppresses inflammatory cytokine production, reduces neutrophil chemotaxis, and inhibits T-cell activation. It also suppresses methyltransferase activity and downregulates interleukin-1 beta signalling. These combined anti-inflammatory effects underlie its efficacy in RA and psoriasis at doses far below those required for cytotoxic effects.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral bioavailability ~60% at ≤30 mg/m²; Tmax 0.75–6 h; absorption decreases at doses >80 mg/m²; food delays but does not significantly reduce extent | Switch to SC/IM if doses exceed ~15–20 mg weekly for reliable absorption; can take with or without food |
| Distribution | Vd(initial) 0.18 L/kg; Vd(ss) 0.4–0.8 L/kg; ~50% protein-bound; highest tissue concentrations in kidney, liver, spleen, skin; does not cross BBB at low doses | Accumulates in third spaces (effusions, ascites) — evacuate before dosing; can be displaced by salicylates, sulfonamides, phenytoin |
| Metabolism | Intracellular polyglutamation (active metabolites retained in tissues); hepatic oxidation by aldehyde oxidase to 7-hydroxymethotrexate (7-OH-MTX, lower solubility); minor intestinal flora metabolism | Polyglutamates persist in cells for weeks, producing prolonged pharmacodynamic effect beyond plasma clearance; 7-OH-MTX may precipitate in renal tubules at high doses |
| Elimination | Primarily renal (80–90% excreted unchanged); t½ 3–10 h (low dose), 8–15 h (high dose); clearance ~84.6 mL/min/m²; glomerular filtration plus tubular secretion and reabsorption | Renal impairment is the most important risk factor for toxicity; hydration and urine alkalinization essential for high-dose protocols; neither hemodialysis nor peritoneal dialysis effectively removes MTX |
Side Effects of Methotrexate
The following incidence data are derived from controlled trials of low-dose oral methotrexate (7.5–15 mg/week) in rheumatoid arthritis (n=128, 12–18 week studies) as reported in the FDA-approved prescribing information, supplemented by long-term observational data. Oncologic regimens carry substantially higher toxicity rates.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Elevated liver function tests (transaminases) | 15% | Usually transient and mild; long-term prevalence of ALT/AST >2× ULN is ~13%; withhold if persistent >3× ULN |
| Nausea and vomiting | 10% | Most common reason patients discontinue; often improves with folic acid, dose splitting, or SC route |
| GI complaints (overall, including anticipatory nausea) | 20–65% | Higher rates in long-term observational data; includes abdominal distress, anorexia, and “methotrexate fog” |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Stomatitis / oral ulcers | 3–10% | May indicate folate depletion; folic acid supplementation reduces risk by up to 79% per RCT data |
| Thrombocytopenia (platelets <100,000/mm³) | 3–10% | More common with renal impairment or concomitant antifolates; hold dose if severe |
| Rash, pruritus, dermatitis | 1–3% | Photosensitivity may occur; advise sun protection |
| Diarrhea | 1–3% | Manageable with dose adjustment; evaluate for infection if persistent |
| Alopecia | 1–3% | Usually mild thinning at low doses; reversible on cessation |
| Leukopenia (WBC <3,000/mm³) | 1–3% | Risk increases with renal impairment, folate deficiency, and co-administration of trimethoprim-sulfamethoxazole |
| Dizziness / fatigue / malaise | 1–3% | Often described as “post-dose fatigue” lasting 24–48 h; usually self-limiting |
| Interstitial pneumonitis | ~1% | Potentially life-threatening; not dose-related; can occur at any time during therapy |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Severe myelosuppression (pancytopenia, agranulocytosis) | Rare (<1%) | Days to weeks after dose; higher risk with renal impairment | Immediate discontinuation; supportive care with G-CSF; consider leucovorin rescue; evaluate renal function |
| Hepatic fibrosis / cirrhosis | ~2.7% after 4 years (meta-analysis) | Chronic — typically after cumulative dose >1.5 g or >2 years of use | Liver biopsy or FibroScan if persistent LFT elevation; discontinue if fibrosis confirmed; risk factors: alcohol, obesity, diabetes, pre-existing liver disease |
| Methotrexate pneumonitis (acute hypersensitivity) | ~1% | Any time; median onset weeks to months | Stop methotrexate immediately; chest imaging; systemic corticosteroids; do not re-challenge |
| Severe renal toxicity (acute kidney injury at high doses) | Uncommon (dose-dependent) | 24–72 h post high-dose infusion | Aggressive hydration, urine alkalinization; glucarpidase for toxic MTX levels with impaired renal function; serial serum MTX monitoring |
| Opportunistic infections (Pneumocystis jirovecii, herpes zoster, disseminated fungal) | Rare | Any time during immunosuppressive therapy | Hold methotrexate; appropriate antimicrobial therapy; consider PJP prophylaxis in high-risk patients on combination immunosuppression |
| Lymphoproliferative disorders (including EBV-related lymphoma) | Very rare | Months to years | Discontinue methotrexate — some cases may regress on cessation; oncology referral |
| Embryo-fetal toxicity (teratogenicity, fetal death) | High risk if exposed during pregnancy | First trimester exposure most critical | Absolute contraindication in pregnancy for non-neoplastic indications; effective contraception mandatory for 6 months (females) and 3 months (males) after last dose |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| GI intolerance (nausea, vomiting, stomatitis) | Most common | Often mitigated by folic acid, SC route, or dose reduction before discontinuation |
| Hepatotoxicity (persistent transaminase elevation) | ~3.7% | Based on long-term studies; risk factors include alcohol, obesity, diabetes |
| Pulmonary toxicity | ~1% | Usually necessitates permanent discontinuation |
| Myelosuppression | <1% | More common in elderly or renal impairment; may be reversible |
Prescribe folic acid 1 mg daily (or 5 mg once weekly on a non-MTX day) to all patients — this reduces GI toxicity and stomatitis risk by up to 79% without compromising efficacy. If oral intolerance persists, switch to subcutaneous administration, which bypasses first-pass GI exposure and often eliminates nausea entirely. Splitting the oral dose (half morning, half evening) may also help. Anti-emetics such as ondansetron can be used for refractory cases. Only discontinue methotrexate for GI intolerance after these interventions have been tried.
Drug Interactions with Methotrexate
Methotrexate is not metabolized via the cytochrome P450 system. Its key interaction pathways involve renal elimination (tubular secretion competition), protein-binding displacement, and pharmacodynamic antifolate synergy. Drugs that reduce renal clearance of methotrexate or potentiate its antifolate effects are the most clinically important interactions.
Monitoring for Methotrexate
-
CBC with differential
Baseline, then weekly ×4, then every 1–3 months
Routine Assess for leukopenia, thrombocytopenia, macrocytic anemia; withhold MTX if WBC <3,000, platelets <100,000, or neutrophils <1,000 -
LFTs (ALT, AST, albumin)
Baseline, then weekly ×4, then every 1–3 months
Routine Withhold if transaminases persistently >3× ULN; declining albumin may signal hepatic fibrosis; assess risk factors (alcohol, obesity, diabetes, hepatitis B/C serology at baseline) -
Renal function (creatinine, eGFR)
Baseline, then every 1–3 months
Routine Renal clearance is the primary elimination pathway; reduce dose or discontinue if eGFR declines significantly; crucial before each high-dose cycle -
Hepatitis B & C serology
Baseline only
Routine Screen before initiation; risk of reactivation of hepatitis B under immunosuppression -
Chest X-ray
Baseline
Routine Establish baseline pulmonary status; repeat if patient develops new cough, dyspnea, or fever during therapy -
Pulmonary function
If new respiratory symptoms
Trigger-based Methotrexate pneumonitis can present at any point; low threshold for CT and pulmonary function testing; stop MTX and do not re-challenge -
Liver biopsy / FibroScan
If persistent LFT elevation or cumulative dose concern
Trigger-based Consider after cumulative dose >1.5 g or if transaminases elevated in >6 of 12 monthly results; non-invasive elastography increasingly preferred over biopsy -
Serum MTX levels (high-dose only)
24, 48, 72 h post high-dose infusion
Routine Guide leucovorin dosing; toxic concentrations (>1 micromol/L at 48 h) require intensified rescue and consideration of glucarpidase -
Pregnancy test
Baseline and as needed
Trigger-based Mandatory before initiation in all females of reproductive potential; confirm effective contraception
Contraindications & Cautions for Methotrexate
Absolute Contraindications
- Pregnancy — for all non-neoplastic indications; known teratogen causing embryo-fetal death and congenital malformations
- Breastfeeding — methotrexate is excreted in breast milk and may cause serious adverse effects in the nursing infant
- Severe hypersensitivity to methotrexate, including prior anaphylaxis
- Severe hepatic impairment — chronic liver disease, cirrhosis, alcoholic hepatitis, or active alcohol use disorder (for RA and psoriasis indications)
- Severe renal impairment (CrCl <30 mL/min) for low-dose use
- Pre-existing severe bone marrow suppression — significant cytopenias at baseline
Relative Contraindications (Specialist Input Recommended)
- Moderate renal impairment (CrCl 30–60 mL/min) — dose reduction and close monitoring required
- Significant pleural effusions or ascites — third-space accumulation delays clearance; evacuate fluid before dosing
- Active peptic ulcer disease or ulcerative colitis — risk of hemorrhagic enteritis and intestinal perforation
- Active infection — hold during acute bacterial, viral, or fungal infections; complete treatment before restarting
- Immunodeficiency syndromes — increased infection risk with further immunosuppression
- Concurrent use of hepatotoxic or nephrotoxic agents — requires careful risk-benefit analysis
Use with Caution
- Elderly patients — age-related decline in renal function increases toxicity risk; start at lower doses
- Obesity, diabetes mellitus — increased risk of hepatic fibrosis with long-term use
- Folate deficiency — amplifies all methotrexate toxicities; correct before or concurrently with therapy
- Neonates and infants — preservative-containing formulations contraindicated due to benzyl alcohol (“gasping syndrome”); use preservative-free only
Embryo-fetal toxicity: Methotrexate can cause fetal death and congenital abnormalities. It is contraindicated in pregnancy for non-neoplastic indications. Females and males of reproductive potential must use effective contraception during and after treatment.
Hepatotoxicity: Potentially fatal liver damage including fibrosis and cirrhosis can occur, typically after prolonged use. Monitor liver function regularly.
Bone marrow suppression: Can cause severe and potentially fatal myelosuppression. Monitor blood counts regularly.
Pulmonary toxicity: Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, may be fatal and can occur at any dose.
Renal toxicity: High-dose methotrexate can cause severe renal damage requiring aggressive hydration, urine alkalinization, and MTX level monitoring.
Serious infections: Potentially fatal opportunistic infections including Pneumocystis jirovecii pneumonia may occur.
Medication errors: Deaths have occurred from inadvertent daily dosing when weekly dosing was intended. Ensure patients understand the weekly schedule for autoimmune indications.
Secondary malignancies: Lymphoproliferative disorders have been reported and may regress upon discontinuation.
GI toxicity: Severe and sometimes fatal GI toxicity including hemorrhagic enteritis and intestinal perforation may occur.
Dermatologic reactions: Severe, occasionally fatal, dermatologic reactions including toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported.
Patient Counselling for Methotrexate
Purpose of Therapy
For autoimmune conditions, explain that methotrexate works by calming the overactive immune system rather than simply treating pain. It takes 4–8 weeks to begin working, and full benefit may not be apparent for 3–6 months. Continued use is important because disease activity typically returns within 3–6 weeks of stopping. Emphasize that the doses used for arthritis and psoriasis are far lower than those used for cancer, and the drug has an extensive safety record when monitored properly.
How to Take
For RA and psoriasis, methotrexate is taken once weekly — NOT daily. Pick a specific day of the week and take all tablets on that day. Taking it daily by mistake has caused fatalities. Take folic acid as directed on non-MTX days. Methotrexate may be taken with or without food, but taking with food may reduce stomach upset. If using a subcutaneous autoinjector, rotate injection sites between abdomen and thighs.
Sources
- Methotrexate Tablets, USP — Full Prescribing Information. West-Ward Pharmaceuticals Corp. Revised 2024. FDA Label Primary source for all approved indications, dosing, boxed warnings, adverse reaction rates, and contraindications for oral formulation.
- Methotrexate Injection — Full Prescribing Information. Pfizer. Revised 2022. Pfizer Label Source for injectable formulation details, high-dose regimen guidance, leucovorin rescue protocols, and intrathecal dosing.
- Methotrexate Injection (Accord) — Full Prescribing Information. Accord Healthcare. 2022. FDA Label Additional injectable formulation label with osteosarcoma dosing details and high-dose supportive care instructions.
- Weinblatt ME, Coblyn JS, Fox DA, et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med. 1985;312(13):818-822. DOI Landmark trial establishing low-dose methotrexate efficacy in RA; foundational for current dosing practice.
- Ridker PM, Everett BM, Pradhan A, et al. (CIRT Investigators). Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2019;380(8):752-762. DOI Large placebo-controlled RCT providing high-quality adverse event rate data for low-dose methotrexate versus placebo.
- Shea B, Swinden MV, Tanjong Ghogomu E, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013;(5):CD000951. DOI Cochrane review confirming folic acid supplementation significantly reduces GI toxicity and stomatitis without compromising MTX efficacy.
- Conway R, Low C, Coughlan RJ, et al. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis. 2009;68(7):1100-1104. DOI Systematic review of MTX safety over >2 years showing favorable long-term profile; source for hepatic fibrosis incidence and discontinuation rates.
- Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2021;73(7):924-939. DOI Current ACR guideline strongly recommending methotrexate as first-line DMARD for moderate-to-high disease activity RA.
- Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis. 2009;68(7):1094-1099. DOI Evidence-based review supporting starting at 15 mg/week with rapid escalation and switch to SC for non-responders.
- Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol. 2020;16(3):145-154. DOI Comprehensive review of the adenosine-mediated anti-inflammatory mechanism of low-dose methotrexate distinct from its antifolate cytotoxic actions.
- Bannwarth B, Péhourcq F, Schaeverbeke T, Dehais J. Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis. Clin Pharmacokinet. 1996;30(3):194-210. DOI Key PK reference for low-dose MTX in RA including bioavailability, protein binding, half-life, clearance, and drug interaction data.
- Herman RA, Veng-Pedersen P, Hall AK, et al. Pharmacokinetics of low-dose methotrexate in rheumatoid arthritis patients. J Pharm Sci. 1989;78(2):165-171. DOI PK study in 41 RA patients establishing clearance (84.6 mL/min/m²), terminal half-life (~6 h), and volume of distribution at steady state.
- van Roon EN, van de Laar MAFJ. Methotrexate bioavailability. Clin Exp Rheumatol. 2010;28(5 Suppl 61):S27-S32. Link Review of oral versus parenteral MTX bioavailability with practical implications for route-switching decisions.