Leflunomide

Disease-modifying antirheumatic drug (DMARD) Isoxazole derivative

Dosage & Administration Guidelines

Species Route Dose Frequency Duration & Clinical Notes
Dog PO Loading dose: 4 mg/kg once daily for 3 days; Maintenance: 2-4 mg/kg once daily Once daily Duration: Long-term; adjust based on clinical response and adverse effects
Notes: Monitor for gastrointestinal upset and hepatotoxicity. Reduce dose if adverse effects occur.
Cat PO Loading dose: 10 mg/cat once daily for 3 days; Maintenance: 2-4 mg/kg once daily (or 10 mg/cat every other day) Once daily or every other day Duration: Long-term; adjust based on response
Notes: Cats are more sensitive to bone marrow suppression; monitor CBC regularly.
Horse PO 2-4 mg/kg once daily Once daily Duration: Long-term; adjust based on response
Notes: Limited data; use with caution and monitor liver enzymes.

Clinical Indications & Species Uses

General Indications
  • Immunosuppressive therapy for immune-mediated diseases
Dog (Canine)
  • Immune-mediated polyarthritis (IMPA)
  • Immune-mediated hemolytic anemia (IMHA) (as adjunctive therapy)
  • Immune-mediated thrombocytopenia (ITP) (as adjunctive therapy)
  • Steroid-responsive meningitis-arteritis (SRMA)
  • Inflammatory bowel disease (IBD) (refractory cases)
  • Meningoencephalomyelitis of unknown origin (MUO)
  • Systemic lupus erythematosus (SLE)
  • Glomerulonephritis (immune-mediated)
Cat (Feline)
  • Immune-mediated hemolytic anemia (IMHA) (as adjunctive therapy)
  • Immune-mediated thrombocytopenia (ITP)
  • Inflammatory bowel disease (IBD) (refractory cases)
  • Eosinophilic granuloma complex (as adjunctive therapy)
  • Feline chronic gingivostomatitis (as adjunctive therapy)
Horse (Equine)
  • Immune-mediated keratitis (IMMK)
  • Uveitis (immune-mediated)
  • Other immune-mediated diseases (limited use)

Pharmacology & Mechanism of Action

Drug Class: Disease-modifying antirheumatic drug (DMARD) | Pharmacological Group: Isoxazole derivative

Mechanism of Action: Leflunomide is a prodrug that is rapidly converted to its active metabolite, teriflunomide (A77 1726), which inhibits dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo synthesis of pyrimidines. This inhibition reduces the proliferation of activated T and B lymphocytes, which are dependent on de novo pyrimidine synthesis for clonal expansion. Additionally, teriflunomide inhibits protein tyrosine kinases and interferes with nuclear factor-κB (NF-κB) signaling, contributing to its anti-inflammatory and immunomodulatory effects. In veterinary medicine, leflunomide is used primarily for its immunosuppressive properties in immune-mediated diseases.

Pharmacodynamics: Leflunomide exerts its immunomodulatory effects by inhibiting lymphocyte proliferation and suppressing the production of autoantibodies. It also reduces the production of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1, IL-6). The drug has a slow onset of action, with clinical effects typically observed after 2-4 weeks of therapy. It is not cytotoxic to resting lymphocytes but selectively inhibits activated lymphocytes, making it a targeted immunosuppressant.

⚡ Pharmacokinetics Summary

Absorption: Leflunomide is well absorbed after oral administration in most species. In dogs, bioavailability is approximately 80-90%. Food may increase absorption and reduce gastrointestinal upset. The prodrug is rapidly converted to teriflunomide in the intestinal wall and liver.
Distribution: Teriflunomide is highly protein-bound (greater than 99%) and has a small volume of distribution. It distributes into tissues, including the skin, and crosses the placenta. In dogs, the volume of distribution is approximately 0.1-0.2 L/kg.
Metabolism: Leflunomide is metabolized to teriflunomide via opening of the isoxazole ring. Teriflunomide undergoes further metabolism, including glucuronidation and oxidation, but the parent drug is not detected in plasma. The liver is the primary site of metabolism.
Excretion: Teriflunomide is eliminated via both biliary and renal routes. In dogs, the elimination half-life is approximately 15-20 days, which is longer than in humans (about 14 days). In cats, the half-life may be shorter, around 10-15 days. Enterohepatic recirculation contributes to the prolonged half-life.
Half-Life: Dogs: 15-20 days; Cats: 10-15 days (estimated); Horses: not well documented
Bioavailability: Oral: approximately 80-90% in dogs; not well studied in other species
Protein Binding: >99% (primarily to albumin)

Available Formulations & Strengths

Oral Tablet 10 mg, 20 mg, 50 mg, 100 mg (PO)

Contraindications & Clinical Warnings

Contraindications:
  • Hypersensitivity to leflunomide or teriflunomide
  • Pregnancy and lactation (teratogenic in animals)
  • Severe hepatic disease
  • Severe renal impairment
  • Active infections (immunosuppression may exacerbate)
Warnings & Clinical Precautions:
  • Use with caution in patients with pre-existing liver disease or elevated liver enzymes.
  • Monitor complete blood count (CBC) and liver enzymes regularly (e.g., every 2-4 weeks initially, then every 3-6 months).
  • May cause immunosuppression; monitor for signs of infection.
  • Use with caution in young animals due to potential effects on growth.
  • In cats, monitor for bone marrow suppression (neutropenia, thrombocytopenia).
  • Do not use in animals with known hypersensitivity to the drug.
  • Avoid use in breeding animals due to teratogenic potential.
  • May cause gastrointestinal upset; administer with food to reduce nausea.
  • Discontinue gradually if possible to avoid disease flare.

Adverse Effects & Reactions

Common:

  • Gastrointestinal upset (vomiting, diarrhea, anorexia)
  • Lethargy
  • Elevated liver enzymes (ALT, ALP)

Serious / Severe:

  • Bone marrow suppression (leukopenia, thrombocytopenia, anemia)
  • Hepatotoxicity (rare but severe)
  • Pancreatitis (rare)
  • Interstitial pneumonia (rare)
  • Peripheral neuropathy (rare)

Rare:

  • Cutaneous reactions (rash, pruritus)
  • Alopecia
  • Weight loss
  • Secondary infections

Key Drug Interactions

Interacting Drug / Class Clinical Effect & Mechanism Severity
Warfarin and other anticoagulants Leflunomide may increase the anticoagulant effect; monitor prothrombin time. Moderate
NSAIDs (e.g., carprofen, meloxicam) Increased risk of gastrointestinal ulceration and bleeding; use with caution. Moderate
Corticosteroids (e.g., prednisone) Additive immunosuppression; monitor for increased risk of infection. Moderate
Cholestyramine or activated charcoal May reduce the half-life of teriflunomide by interrupting enterohepatic recirculation; used in overdose management. Mild
Rifampin May increase the metabolism of leflunomide, reducing its efficacy. Moderate

Overdose & Toxicity Management

Signs of Toxicity:

  • Severe gastrointestinal signs (vomiting, diarrhea)
  • Bone marrow suppression (pancytopenia)
  • Hepatotoxicity
  • Neurological signs (ataxia, seizures) in severe cases

Emergency Treatment Protocol: There is no specific antidote. Treatment is symptomatic and supportive. Administer activated charcoal or cholestyramine to reduce absorption and interrupt enterohepatic recirculation. Monitor CBC, liver enzymes, and renal function. Provide fluid therapy and supportive care. In severe cases, consider blood transfusions or colony-stimulating factors for bone marrow suppression.

Food Animal Withdrawal Times

Not approved for use in food animals; withdrawal times not established. Do not use in animals intended for food.

Storage, Handling & Regulatory Information

Storage Temperature: Store at room temperature (20-25°C, 68-77°F)

Handling & Special Conditions: Keep in a tightly closed container, protect from moisture.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: Not approved for veterinary use; approved for human use (rheumatoid arthritis).

Extra-Label (Off-Label) Use: In the US, leflunomide is not FDA-approved for veterinary use; use in animals is extra-label. Must follow AMDUCA regulations for food animals (not applicable as not used in food animals).

Clinical Pearls & Practice Notes

💡 Clinical Insights: Leflunomide is a valuable immunosuppressive agent in veterinary medicine, particularly for immune-mediated diseases in dogs and cats. It is often used as a steroid-sparing agent or in combination with corticosteroids. The drug has a slow onset of action, so it is not suitable for acute crises. Monitoring is essential due to potential bone marrow suppression and hepatotoxicity. In dogs, a loading dose is recommended to achieve therapeutic levels quickly. In cats, lower doses are used due to increased sensitivity. Gastrointestinal side effects can be managed by administering with food or using antiemetics. Due to its long half-life, drug interactions and adverse effects may persist after discontinuation; cholestyramine can be used to accelerate elimination if needed. Always inform pet owners about the need for regular blood tests and potential side effects.

References & Literature

  • 📚 Plumb's Veterinary Drug Handbook
  • 📚 Papich Veterinary Pharmacology and Therapeutics
  • 📚 Compendium of Veterinary Products (CVP)