II. Indications

  1. Rheumatoid Arthritis
    1. First line DMARD instead of Methotrexate
    2. Has been used in combination with Methotrexate (but increased hepatotoxicity risk)
  2. Psoriatic Arthritis (off-label use)

III. Contraindications

  1. Hepatotoxicity risk factors including severe hepatic insufficiency
  2. Renal Insufficiency
  3. Severe Immunodeficiency
  4. Myelosuppression
  5. Serious infections
  6. Pregnancy

IV. Mechanism

  1. Pyrimidine inhibitor
  2. T-Cell Activation and proliferation inhibitor
  3. Similar to Methotrexate in effects
  4. Onset of action in 1-2 months

V. Dosing

  1. Start 20 mg orally once daily
  2. Loading dose: 100 mg orally daily for 3 days
    1. Loading dose is avoided in most cases (rarely used)
    2. Loading dose increases adverse effects (e.g. hepatotoxicity)
    3. Most prescribers start with maintenance dosing
  3. Maintenance: 10 mg orally daily (or 20 mg orally every other day)
  4. Higher Dose (if inadequate relief at lower dose): 20 mg orally daily

VI. Pharmacokinetics

  1. Half-Life: 18 days

VII. Adverse Effects

  1. Nausea (may limit use)
  2. Diarrhea
  3. Headache
  4. Alopecia
  5. Hepatotoxicity
    1. Liver injury occurs in 1 in 200 patients
    2. Increased Liver transaminases (e.g. AST, SGOT)
    3. Increased hepatotoxicity risk when combined with Methotrexate or Immunosuppressants
  6. Interstitial Lung Disease
    1. Lung injury (observe for new onset cough)
  7. Other rare, serious adverse effects
    1. Lymphoma
    2. Hematologic (Agranulocytosis, Pancytopenia, Thrombocytopenia)
    3. Stevens Johnson Syndrome
    4. Severe Hypertension
  8. Overdose or pregnancy detected
    1. See other references or contact poison control for protocol
    2. Administer Activated Charcoal 50 grams orally or by Nasogastric Tube every 6 hours for 24 hours
    3. Administer Cholestyramine 8 grams orally three times daily for up to 11 days
    4. May follow Teriflunomide levels
      1. May direct repeat charcoal and Cholestyramine courses if levels >0.02 mg/L

VIII. Safety

  1. Avoid in Lactation
  2. Pregnancy Category X
    1. Avoid in pregnancy (Teratogenic)
    2. Screen for pregnancy before use and use reliable Contraception

IX. Drug Interactions

  1. Warfarin
    1. Increases INR
  2. Drugs that increase Leflunomide levels
    1. Rifampin
  3. Drugs that decrease Leflunomide levels
    1. Cholestyramine

X. Monitoring

  1. Labs
    1. Aspartate Transaminase (SGOT, AST)
    2. Complete Blood Count with Platelet Count
  2. History
    1. Ask about new onset cough
  3. Timing
    1. Check baseline and then monthly for 6 months
    2. Check every 6-8 weeks afterward

XI. Efficacy

  1. Comparable to Methotrexate
  2. Used with Methotrexate for maximal effect

XIII. References

  1. Hamilton (2020) Tarascon Pocket Pharmacopoeia
  2. Sharp (2000) Arthritis Rheum 43:495-505 [PubMed]

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Related Studies

Cost: Medications

leflunomide (on 12/21/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
LEFLUNOMIDE 10 MG TABLET Generic $0.44 each
LEFLUNOMIDE 20 MG TABLET Generic $0.50 each

Ontology: leflunomide (C0063041)

Definition (NCI) A derivative of isoxazole used for its immunosuppressive and anti-inflammatory properties. As a prodrug, leflunomide is converted to an active metabolite, A77 1726, which blocks dihydroorotate dehydrogenase, a key enzyme of de novo pyrimidine synthesis, thereby preventing the expansion of activated T lymphocytes. This agent also inhibits various protein tyrosine kinases, such as protein kinase C (PKC), thereby inhibiting cell proliferation. (NCI04)
Definition (NCI_NCI-GLOSS) An anticancer drug that works by inhibiting a cancer cell growth factor.
Definition (PDQ) A derivative of isoxazole used for its immunosuppressive and anti-inflammatory properties. As a prodrug, leflunomide is converted to an active metabolite, A77 1726, which blocks dihydroorotate dehydrogenase, a key enzyme of de novo pyrimidine synthesis, thereby preventing the expansion of activated T lymphocytes. This agent also inhibits various protein tyrosine kinases, such as protein kinase C (PKC), thereby inhibiting cell proliferation. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=42253&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=42253&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C1128" NCI Thesaurus)
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C045463
SnomedCT 109143003, 386981009
LNC LP34970-1, MTHU017708
English 4-Isoxazolecarboxamide, 5-methyl-N-(4-(trifluoromethyl)phenyl)-, leflunomide, N-(4-trifluoromethyphenyl)-5-methylisoxazole-4-carboxamide, 4-Isoxazolecarboxamide, 5-Methyl-N-(4-(trifluoromethyl)phenyl)-, leflunomide (medication), LEFLUNOMIDE, leflunomide [Chemical/Ingredient], Leflunomide (product), Leflunomide (substance), Leflunomide
Spanish leflunomida (producto), leflunomida (sustancia), leflunomida

Ontology: Arava (C0718644)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C045463
English arava, Hoechst Brand of Leflunomide, Aventis Behring Brand of Leflunomide, Aventis Brand of Leflunomide, Aventis Pharma Brand of Leflunomide, Arava