Methotrexate
Methotrexate sodium
Also known as: Rheumatrex · Trexall · Methotrexate LPF · MTX · Amethopterin · 4-Amino-4-deoxy-10-methylpteroyl-L-glutamic acid · 4-Amino-10-methylfolic acid · CL-14377 · alpha-methopterin · methotrexatum · metotrexato · NSC-740 · WR-19039
Reviewed by the VetSheet Veterinary TeamUpdated Apr 5, 2026Evidence-based veterinary reference
This dose is based on body surface area (mg/m²). Convert body weight to body surface area before dosing.
Doses are a clinical reference for licensed veterinary professionals. Always confirm against the current label and the individual patient.
Dosing by species
🌎 NA — North America🌍 EU — Europe
Dogs
| Indication | Dose | Route | Frequency | Duration | Region |
|---|---|---|---|---|---|
| As part of the LMP protocol for maintenance of canine lymphoma | 2.5-5 mg/m2 PO twice a week | PO | twice a week | — | 🌎 NA |
| In combination with other antineoplastics (per protocol) | 5 mg/m2 PO twice weekly or 0.8 mg/kg IV every 21 days; alternatively 2.5 mg/m2 PO daily | PO/IV | twice weekly, every 21 days, or daily | — | 🌎 NA |
- As part of the LMP protocol for maintenance of canine lymphoma: Given with Chlorambucil 20 mg/m2 PO every 15 days and Prednisone 20 mg/m2 PO every other day. When Vincristine is added it is at a dose of 0.5-0.7 mg/m2 and is given every 15 days alternating weeks with the chlorambucil.
Cats
| Indication | Dose | Route | Frequency | Duration | Region |
|---|---|---|---|---|---|
| For susceptible neoplastic diseases (usually as part of a multi-drug protocol) | 2.5 mg/m2 PO 2-3 times weekly; 0.3-0.8 mg/m2 IV every 7 days | PO/IV | 2-3 times weekly (PO) or every 7 days (IV) | — | 🌎 NA |
| For non-suppurative cholangitis/cholangiohepatitis (CCHC) syndrome with fibrosis | A total dose of 0.4 mg per cat total dose given on one day in three divided doses: 0.26 mg at hour zero, 0.13 mg at the 12 and 24 hour dosing. Repeat every 7-10 days. | PO | Divided over 24 hours, repeated every 7-10 days | — | 🌎 NA |
- For non-suppurative cholangitis/cholangiohepatitis (CCHC) syndrome with fibrosis: Use in conjunction with ursodeoxycholic acid (15 mg/kg PO q24h) and folate (0.25 mg/kg PO q24h).
Doses are a clinical reference for licensed veterinary professionals. Always confirm against the current label and the individual patient.
Overview
Methotrexate (MTX) is a potent folic acid antagonist used in veterinary oncology primarily for the treatment of lymphoproliferative disorders (such as lymphoma) and certain solid tumors in dogs and cats.
Beyond its antineoplastic properties, it possesses significant immunosuppressive capabilities, making it a valuable option for refractory immune-mediated conditions, such as feline non-suppurative cholangitis/cholangiohepatitis that has not responded to standard prednisolone or chlorambucil therapy.
Clinical Pearl: Because MTX has a very narrow therapeutic index and relies heavily on renal clearance, patient hydration and kidney function are paramount to preventing severe toxicity. It is highly toxic to rapidly dividing cells, meaning the gastrointestinal epithelium and bone marrow are particularly susceptible to collateral damage.
Mechanism of action
Methotrexate is an S-phase specific antimetabolite. It acts by competitively and irreversibly inhibiting the enzyme dihydrofolate reductase (DHFR).
- Folic acid → (via DHFR) → Dihydrofolate → (via DHFR) → Tetrahydrofolate (active form).
- By blocking DHFR, MTX prevents the reduction of dihydrofolate to tetrahydrofolate.
- Tetrahydrofolate is an essential cofactor for the synthesis of purines and pyrimidines (specifically thymidylate).
- The depletion of these precursors halts DNA, RNA, and protein synthesis, ultimately leading to apoptosis in rapidly proliferating cells (e.g., neoplasms, bone marrow, GI tract epithelium).
Note: DHFR has a much greater affinity for MTX than for folic acid. Therefore, coadministration of folic acid will not reverse MTX toxicity. Leucovorin calcium (a derivative of tetrahydrofolic acid that bypasses the blocked enzyme) is required as a rescue agent.
Safety & warnings
Contraindications
- Preexisting bone marrow depression
- Severe hepatic insufficiency
- Severe renal insufficiency
- Hypersensitivity to the drug
- Pregnancy (Teratogenic/Embryotoxic - FDA Category X)
- Nursing mothers
- Pre-existing severe bone marrow suppression
- Severe renal impairment
- Severe hepatic impairment
- Pregnancy and lactation (teratogenic and embryotoxic)
- Patients with significant third-space fluid accumulations (e.g., ascites, pleural effusion)
Adverse effects
- Nausea
- Inappetence (especially in cats)
- GI toxicity (ulcers, mucosal sloughing, stomatitis)
- Hematopoietic toxicity / Myelosuppression (nadir at 4-6 days)
- Hepatopathy
- Renal tubular necrosis
- Depigmentation
- Pulmonary infiltrates and fibrosis
- CNS toxicity (encephalopathy) if given intrathecally
- Anaphylaxis (rare)
- Myelosuppression (neutropenia, thrombocytopenia, anemia)
- Gastrointestinal toxicity (anorexia, vomiting, diarrhea, stomatitis)
- Hepatotoxicity (elevated liver enzymes)
- Nephrotoxicity (especially at high doses due to tubular precipitation)
- Alopecia (rare in most animals, but possible in continuously growing coats)
Precautions
Use with extreme caution in patients susceptible to or with preexisting clinical signs of MTX adverse reactions. Handling Precautions: Wear gloves or immediately wash hands after handling. Gloves are particularly important if handling split, broken, or crushed tablets. Preparation of intravenous solutions should ideally be performed in a vertical laminar flow hood to avoid human exposure. Teratogenic and may affect spermatogenesis.
Drug interactions
Prolonged PO administration (>2 weeks) may inhibit MTX metabolism
Given concomitantly with MTX may decrease MTX efficacy
Potential for increased risk for hepatic toxicity
May displace MTX from plasma proteins increasing risk for toxicity, but also may reduce MTX absorption and enterohepatic recirculation
May have synergistic action with MTX, but alter the renal elimination of MTX
May increase MTX levels
May reduce MTX efficacy, but folate deficiency increases MTX toxicity
May decrease the absorption of oral methotrexate if given concomitantly
Severe hematologic and GI toxicity risk; use caution in dogs also on MTX
May decrease MTX renal elimination
May inhibit the tubular secretion of MTX and increase its half-life
A similar folic acid antagonist; may increase MTX toxicity and should not be given to patients receiving MTX
Potential for increased risk for hepatic toxicity
Potential for increased risk for hepatic toxicity
May displace MTX from plasma proteins increasing risk for toxicity
May displace MTX from plasma proteins increasing risk for toxicity, but also may reduce MTX absorption and enterohepatic recirculation
MTX may reduce theophylline elimination
Rarely, may increase myelosuppression of MTX
Live virus vaccines should be used with caution, if at all during therapy
Decreased renal clearance of methotrexate, leading to increased serum levels and severe toxicity.
Additive antifolate effects, significantly increasing the risk of severe bone marrow suppression.
May delay the elimination of methotrexate.
Monitoring
- Efficacy of treatment
- Clinical signs of GI irritation and ulceration
- Complete blood counts (with platelets) weekly early in therapy, then every 4-6 weeks (Discontinue if WBC <4000/mm3 or platelets <100,000/mm3)
- Baseline and ongoing renal function tests
- Baseline and ongoing hepatic function tests (liver enzymes)
- Complete Blood Count (CBC) - baseline and prior to each dose (monitor for nadir)
- Renal function panel (BUN, Creatinine, Urinalysis)
- Hepatic enzymes (ALT, AST, ALP, Bilirubin)
- Clinical signs of gastrointestinal toxicity (vomiting, diarrhea, anorexia)
- Hydration status
Pharmacokinetics
Half-life
Absorption
Well absorbed from the GI tract after oral administration of dosages <30 mg/m2 with a bioavailability of about 60%. Peak levels occur within 4 hours after oral dosing, and between 30 minutes and 2 hours after IM injection.
Distribution
Widely distributed in the body and actively transported across cell membranes. Highest concentrations in kidneys, spleen, gallbladder, liver, and skin. Does not reach therapeutic levels in CSF unless given intrathecally. About 50% bound to plasma proteins and crosses the placenta.
Metabolism
Minimal hepatic metabolism is noted; primarily excreted unchanged.
Elimination
Excreted almost entirely by the kidneys via both glomerular filtration and active transport.
Overdose
Acute overdosage in dogs is associated with severe exacerbations of adverse effects, particularly myelosuppression and acute renal failure. Acute tubular necrosis occurs secondary to drug precipitation in the renal tubules.
- Toxicity Thresholds: In dogs, the maximally tolerated dose is reported to be 0.12 mg/kg q24h for 5 days. A dose of 10 mg/kg is considered lethal if leucovorin rescue is not performed.
- Decontamination: Empty the gut and prevent absorption using standard protocols if ingestion is recent. Oral neomycin has been suggested to help prevent intestinal absorption.
- Renal Protection: Forced alkaline diuresis should be considered to minimize renal damage. Maintain urine pH between 7.5-8 by adding 0.5-1 mEq/kg of sodium bicarbonate per 500 mL of IV fluid.
- Antidote: Leucovorin calcium is the specific therapy for MTX overdoses. It must be given as soon as possible (preferably within the first hour, definitely within 48 hours). Dogs treated with leucovorin at 15 mg/m2 every 3 hours IV for 8 doses, then IM q6h for 8 doses were able to tolerate very high MTX doses.
Available products
Formulations
- Tablets
- Injection solution
- Powder for injection
- 2.5 mg oral tablet
- 10 mg oral tablet
Human-labeled
- Methotrexate Sodium Tablets (plain & scored): 2.5 mg, 5 mg, 7.5 mg, 10 mg & 15 mg
- Methotrexate Sodium Injection: 25 mg/mL (as base) in various vial sizes
- Methotrexate Powder for Injection, lyophilized: 1 gram preservative free in single-use vials
- Matrex 2.5 mg tablets
- Methotrexate 2.5 mg tablets
- Methotrexate 10 mg tablets
Regulatory status
Human authorized products often used off-label under the cascade.
Prescription Only Medicine. Handled under cascade regulations.
No regulatory data for: 🇺🇸 US · 🇭🇰 HK · 🇹🇼 TW · 🇯🇵 JP · 🇰🇷 KR · 🇦🇺 AU
Storage & stability
Methotrexate sodium tablets should be stored at room temperature (15-30°C) in well-closed containers and protected from light. The injection and powder for injection should be stored at room temperature (15-30°C) and protected from light.
Client information
WARNING: CHEMOTHERAPY AGENT This medication is highly toxic and can be hazardous to humans if handled improperly.
- Handling Safety: Always wear disposable gloves when administering tablets, especially if they are crushed or split. If gloves are not used, wash hands thoroughly immediately after handling. Pregnant women or immunocompromised individuals should avoid handling this drug.
- Toxicity Risks: You must be aware of the possibilities of severe toxicity developing from this drug, including drug-related mortality.
- When to Call the Vet: Contact your veterinarian immediately if your pet exhibits clinical signs of profound depression, lethargy, abnormal bleeding (including bloody diarrhea, dark tarry stools), bruising, vomiting, or loss of appetite.
- Nursing: Do not allow pets on this medication to nurse offspring; switch to a milk replacer.
VetSheet drug reference is intended for licensed veterinary professionals as a clinical decision-support aid, not a substitute for professional judgement or the manufacturer’s current label.