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Lisa Singer, VMD, DACVIM, Veterinary Specialist Services

Pharmacology & Medications

|January 2016|Peer Reviewed

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In dogs, leflunomide is infrequently used as an immunomodulatory and immunosuppressive drug and an alternative or adjunct to corticosteroid therapy for immune-mediated and histiocytic disease.1 

Mechanisms of Action

  • Leflunomide works as an immunomodulatory drug by inhibiting the enzyme dihydroorotate dehydrogenase, which is involved in pyrimidine synthesis.
    • Decreases lymphocyte proliferation
      • Affects both T and B cells
      • Decreases antibody production
    • Also inhibits cytokine production and tyrosine kinase-mediated signal transduction for a stronger immunosuppressant effect   
  • Leflunomide is rapidly metabolized to teriflunomide, the active metabolite responsible for the drug’s clinical effects.
    • Metabolism occurs rapidly in the GI tract and liver after oral administration.
    • The half-life is ≈1 day after oral administration in dogs and ≈2.5 days in cats.2,3
    • Because of the need for hepatic cytochrome p450 enzyme metabolism, leflunomide should be used with caution in animals with hepatic disease.4 

Clinical Applications

  • Leflunomide was originally studied to prevent renal transplantation rejection in dogs.5 
    • By inhibiting B and T lymphocytes, this drug reduces T-cell–mediated graft destruction in transplantation patients and prevents alloantibody production. 
    • Doses >4 mg/kg once a day in dogs can prevent transplant rejection, but adverse reactions (eg, profound anemia from bone marrow supression, anorexia, vomiting, diarrhea)5 can be severe, and the drug is not well tolerated.
    • Leflunomide inhibits feline herpesvirus type 1 (FHV-1) replication in vitro.6
      • This drug may be an alternative to calcineurin-based immunosuppression in feline renal transplantation patients.6     
  • Leflunomide is rarely used as a primary or lone immunosuppressive agent in dogs.
    • The first cases evaluating leflunomide described administration to dogs as part of immunosuppressive therapy during experimental renal transplantation.5,7-9
    • This drug has been used as a single agent to achieve clinical remission in multiple cases of immune-mediated polyarthritis in dogs.10
    • In individual cases, leflunomide has reportedly had success as adjunctive treatment of immune-mediated disease (eg, IMHA, ITP, polymyositis, Evans syndrome, pemphigus foliaceus) and been used to treat inflammatory brain disease and systemic histiocytosis.1,11,12

Leflunomide has been used as a single agent to achieve clinical remission in multiple cases of immune-mediated polyarthritis in dogs.10

  • Leflunomide can be used as an adjunctive immunosuppressant to induce remission when glucocorticoids are ineffective, side effects are unacceptable, or concurrent clinical disease necessitates alternative long-term drug choices.
    • It has been safely combined with prednisolone, cyclosporine, and IV immunoglobulin in dogs.1,8,11
    • Caution is advised when using this drug with azathioprine or other medications that induce hepatic cytochrome p450 enzymes because of the risk for hepatotoxicity.
      • Conversion of leflunomide to teriflunomide in the human liver is mediated by p450 enzymes; the exact mechanism in dogs is still unknown.4


  • In dogs, 3-4 mg/kg PO once a day is recommended.2 A loading dose is not recommended.
    • Because this drug can take 15 to 18 days to reach a steady state based on pharmacokinetic projections, a tapering course of glucocorticoids may be indicated if more rapid induction of remission is needed.2
      • Administration should be continued at least 4 to 6 weeks, then slowly tapered. Abrupt discontinuation is not recommended.
      • No consensus on tapering this drug exists. In the author’s clinical experience, tapering by dose reduction (eg, 20%-25% every 3-4 weeks) or by skipping treatment on some days (eg, 3 days on, 1 day off) can be effective.
    • Little information on the use of this drug in dogs is available.  
  • In cats, 10 mg/cat PO once a day is tolerated clinically.13 
    • Although uncommonly used, leflunomide treatment of feline erosive polyarthritis in combination with methotrexate has reportedly been successful.13
    • Dose reductions to 10 mg/cat every 2 to 3 days are suggested once disease has been controlled clinically.  
  • Further investigation is needed to determine ideal therapeutic drug levels in dogs and cats.
    • A high-performance liquid chromatography assay for drug monitoring has been described.
      • Drug monitoring for the active metabolite teriflunomide at 12- or 24-hour trough levels in dogs and cats is available from the clinical pharmacology laboratory at Auburn University.14,15
      • Trough levels of 20 µg/mL have been shown to suppress lymphocytes in vitro.5

Adverse Effects & Cautions

  • In dogs, laboratory changes have included anemia, leukopenia, thrombocytopenia, and hypercholesterolemia.
    • Reported clinical side effects include hematemesis, hematochezia, lethargy, and myelosuppression.
      • Long-term effects are not well-known.
    • Anecdotal reports of severe bone marrow necrosis have been associated with leflunomide therapy in dogs.
    • Rarely, cutaneous drug reactions have been noted on the face, foot pads, neck, and trunk.
      • These rapidly resolve when the drug is discontinued (anecdotal).
    • Hepatotoxicity and liver enzyme elevations have been reported in humans.16,17  
  • In cats, known side effects include sedation and vomiting.  
  • Routine CBC and serum chemistry profile monitoring is recommended after 2 weeks, then every 4 to 6 weeks.

FHV-1 = feline herpesvirus type 1, GI = gastrointestinal, CBC = complete blood count, IMHA = immune-mediated hemolytic anemia, ITP = immune-mediated thrombocytopenia

References and Author Information

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

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