Methotrexate

TREXALL

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What it isDHFR inhibitor that depletes folate; rheumatoid arthritis, psoriasis, and malignancy.

Why this oneIt is the inexpensive anchor DMARD in rheumatoid arthritis and improves response when combined with biologics.

What limits itA daily-for-weekly dosing error can be fatal; supplement folate, monitor counts and organ function, and avoid trimethoprim.

FDA-approved for

cancer/RA/psoriasis (~1953)

Off-label

ectopic pregnancy
inflammatory bowel disease

FDA label

Read the full label on DailyMed ↗

BOXED WARNING Embryo-fetal toxicity incl. fetal death (contraindicated in pregnancy for non-neoplastic disease); severe hypersensitivity/anaphylaxis; serious/fatal adverse reactions (bone marrow, GI, liver, lung, skin, kidney); fatal medication errors — once-weekly, not daily.

FDA dosing	Population	Start	Target	Max
Acute lymphoblastic leukemia (maintenance)	adult	20 mg/m2 PO once weekly	adjust to ANC/platelets
Mycosis fungoides	adult	25-75 mg PO once weekly (monotherapy) or 10 mg/m2 PO twice weekly (combination)
Relapsed/refractory non-Hodgkin lymphoma	adult	2.5 mg PO 2-4x/week (metronomic combination)		10 mg/week
Rheumatoid arthritis	adult	7.5 mg PO once weekly	adjust to response	>20 mg/week increases serious adverse reaction risk
Polyarticular juvenile idiopathic arthritis	pediatric	10 mg/m2 PO once weekly	adjust to response	>30 mg/m2/week increases serious adverse reaction risk
Psoriasis	adult	10-25 mg PO once weekly	lowest effective dose	30 mg/week

Renal CLcr <90 mL/min: increased risk of adverse reactions; monitor closely and reduce dose or discontinue

Hepatic Undefined (PK/safety unknown; may be at increased risk of adverse reactions)

Once-weekly dosing; medication errors with daily dosing have been fatal

Instructions

Dose ONCE WEEKLY (not daily) — daily dosing has caused death; verify regimen
Verify pregnancy status in females of reproductive potential before starting
Administer folic or folinic acid to reduce adverse reactions
Do not give to patients unable to swallow a tablet
Cytotoxic drug — follow special handling/disposal

Contraindications

Pregnancy (for non-neoplastic diseases)
History of severe hypersensitivity reactions (incl. anaphylaxis) to methotrexate

Cautions

Myelosuppression
Gastrointestinal toxicity
Hepatotoxicity
Pulmonary toxicity
Dermatologic reactions
Renal toxicity
Serious infections
Neurotoxicity
Secondary malignancies
Tumor lysis syndrome
Increased risk with third-space fluid accumulation

Adverse reactions

Ulcerative stomatitis
Leukopenia
Nausea
Abdominal distress
Infection, malaise, fatigue, chills, fever, dizziness

Pregnancy Contraindicated (non-neoplastic disease); causes embryo-fetal toxicity and fetal death; skull/CNS/limb anomalies with first-trimester exposure

Lactation Undefined

⚠ BOXED WARNING

Serious toxic reactions and embryo-fetal toxicity

Cost, est. cash$5,000–$30,000+/month or cycle

Generic entry2035 est.

Classes and tags

Clinical profile

Therapeutic safety burden4 / 4

Overdose danger4 / 4

Weight-gain liability0 / 4

Sedation liability0 / 4

QT / Torsades0 / 4

Direct muscarinic antagonism0 / 4

Embryofetal risk4 / 4

Legacy pregnancy categoryX

Defining liabilityPotentially fatal myelosuppression, hepatotoxicity, pneumonitis and dosing-error toxicity; weekly dosing errors are especially dangerous.