Leflunomide
N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide
Also known as: Arava · HW A 486 · RS 34821 · SU 101
Reviewed by the VetSheet Veterinary TeamUpdated Apr 5, 2026Evidence-based veterinary reference
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 |
|---|---|---|---|---|---|
| Immunosuppressive as part of a protocol (with cyclosporine) following organ transplant | 4-6 mg/kg PO q24h and then to maintain trough plasma levels of 20 micrograms/mL | PO | q24h | — | 🌎 NA |
| Adjunctive immunosuppressive for immune-mediated hemolytic anemia | 4 mg/kg PO q24h | PO | q24h | — | 🌎 NA |
| Treatment of systemic and cutaneous reactive histiocytosis | 2-4 mg/kg PO once daily to attain trough levels of 20 micrograms/mL | PO | q24h | — | 🌎 NA |
| Treatment of Evans' Syndrome in a diabetic dog | 2 mg/kg PO q12h | PO | q12h | Decreased by 25% every 4 weeks for first 4 months, then every 8 weeks | 🌎 NA |
- Treatment of Evans' Syndrome in a diabetic dog: In combination with human intravenous immunoglobulin (hIVIg). Target trough level approx 20 micrograms/mL.
Cats
| Indication | Dose | Route | Frequency | Duration | Region |
|---|---|---|---|---|---|
| Rheumatoid arthritis | Initially, leflunomide at 10 mg (total dose) PO once daily and methotrexate at 2.5 mg (total dose) PO three times on one day per week. When significant improvement occurs, reduce doses of leflunomide to 10 mg PO twice weekly and methotrexate to 2.5 mg PO once weekly. | PO | q24h initially, then twice weekly | — | 🌎 NA |
- Rheumatoid arthritis: Used in combination with methotrexate.
Doses are a clinical reference for licensed veterinary professionals. Always confirm against the current label and the individual patient.
Overview
Leflunomide is a disease-modifying antirheumatic drug (DMARD) used off-label in veterinary medicine as a potent, steroid-sparing immunosuppressant.
- Clinical Uses: It is primarily utilized in dogs for refractory immune-mediated conditions such as immune-mediated hemolytic anemia (IMHA), immune-mediated polyarthritis (IMPA), systemic and cutaneous reactive histiocytosis, and granulomatous meningoencephalitis (GME). It is also used in transplant rejection protocols.
- Feline Use: Occasionally used in combination with methotrexate for feline rheumatoid arthritis.
- Clinical Pearl: Because leflunomide targets de novo pyrimidine synthesis (which activated lymphocytes heavily rely upon), it provides a targeted immunosuppressive effect. However, its active metabolite has an exceptionally long half-life, meaning toxicity can persist long after the drug is discontinued.
Mechanism of action
Leflunomide is a prodrug that is rapidly converted in the intestinal mucosa and liver to its active metabolite, teriflunomide (A77 1726 or M1).
- Mechanism: Teriflunomide reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH).
- Pathway: Inhibition of DHODH → prevents the formation of ribonucleotide uridine monophosphate (rUMP) → decreases de novo pyrimidine synthesis → decreases DNA and RNA synthesis.
- Result: This induces G1 cell cycle arrest, profoundly inhibiting the proliferation of rapidly dividing autoimmune T-cells and the production of autoantibodies by B-cells.
Safety & warnings
Contraindications
- Pregnancy (Category X teratogen)
- Hypersensitivity to leflunomide
- Pre-existing immunodeficiency
- Significant renal impairment
- Pregnancy and lactation
- Pre-existing severe bone marrow suppression
- Severe hepatic impairment
- Active severe infections
Adverse effects
- Decreased appetite
- Lethargy
- Lymphopenia
- Alopecia
- Rash
- Hepatotoxicity
- Severe dermatologic reactions (Toxic Epidermal Necrolysis, Stevens-Johnson syndrome - reported in humans)
- Gastrointestinal upset (vomiting, diarrhea, anorexia)
- Bone marrow suppression (leukopenia, anemia, thrombocytopenia)
- Unexplained bleeding
Precautions
Teratogenicity Warning: Leflunomide is an FDA Category X teratogen. It must not be used in pregnant animals, and pregnant women should not handle this medication.
Prolonged Half-Life: The active metabolite (A77 1726) can persist in the body for up to 2 years after discontinuation. If severe toxicity occurs, a washout procedure using cholestyramine or activated charcoal is required.
Use with extreme caution in patients with hepatic disease, renal impairment, or pre-existing immunodeficiency.
Drug interactions
Can increase elimination and decrease A77 1726 drug concentrations; used for rapid washout.
Can increase elimination and decrease A77 1726 drug concentrations; used for rapid washout.
Increased risk for hepatotoxicity when used concurrently.
Increased risk of adverse effects and elevated ALT.
Leflunomide can increase phenytoin levels.
Can increase A77 1726 peak levels.
Should be used with extreme caution, if at all, due to immunosuppression.
Leflunomide may increase INR.
Increased risk of severe immunosuppression and bone marrow toxicity
Risk of disseminated infection due to immunosuppression
Monitoring
- Complete Blood Count (CBC) for hematologic toxicity (lymphopenia, anemia)
- Liver enzymes (ALT, AST, ALP) for hepatotoxicity
- Trough levels of A77 1726 (Target is 20 micrograms/mL)
- Clinical signs of secondary infections
- Gastrointestinal tolerance
Pharmacokinetics
Half-life
Absorption
Rapidly converted to active metabolite A77 1726 (M1) in the GI mucosa and liver. Peak levels occur 6-12 hours post-dose. Food does not affect bioavailability.
Distribution
Highly bound to albumin (>99%).
Metabolism
Converted to A77 1726 in GI mucosa/liver. Further degraded in the liver as glucuronides and an oxalinic acid compound. Conversion to toxic metabolites is reported to be slower in cats than in dogs.
Elimination
Excreted in the urine and bile. The active metabolite can be detectable up to 2 years after discontinuation.
Overdose
Acute toxicologic studies in mice and rats demonstrate minimally toxic doses of 200 mg/kg and 100 mg/kg, respectively.
Washout Protocol: Because of the extremely long half-life of the active metabolite, cholestyramine or activated charcoal administration is highly recommended to accelerate elimination in cases of overdose or severe toxicity. Contact an animal poison control center for specific washout protocols.
Available products
Formulations
- Tablets
- 10 mg tablet
- 15 mg tablet
- 20 mg tablet
- 100 mg tablet
Human-labeled
- Leflunomide Tablets: 10 mg & 20 mg (Arava®, generic)
- Arava 10 mg tablets
- Arava 15 mg tablets
- Arava 20 mg tablets
- Arava 100 mg tablets
Regulatory status
POM (Prescription Only Medicine)
POM (Prescription Only Medicine)
No regulatory data for: 🇺🇸 US · 🇭🇰 HK · 🇹🇼 TW · 🇯🇵 JP · 🇰🇷 KR · 🇦🇺 AU
Storage & stability
Store tablets at room temperature (15-30°C) and protect from light.
Client information
- Experimental Use: This medication is relatively experimental when used in veterinary patients. Contact your veterinarian immediately if any unusual effects (such as decreased appetite, lethargy, or vomiting) are noted.
- Safe Handling: This drug is a known teratogen (can cause birth defects). Pregnant women or women trying to conceive should not handle this medication. Always wear gloves when handling, and do not crush or split the tablets.
- Cost: Treatment can be very expensive, though prices have decreased with the availability of generic formulations.
- Nursing: Do not allow nursing pets to feed if the mother is receiving this drug; use 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.