Contents

Search

leflunomide; teriflunomide (Arava)

Tradname: Arava. Pressure from Public Citizen on FDA to remove Arava from US market. Indications: - rheumatoid arthritis [7] a) may be used concurrently with NSAIDs & low-dose glucocorticoids b) alternative to cytotoxic agents (methotrexate) Contraindications: - pregnancy category: X - teratogenic (do not use during pregnancy) - women using leflunomide who plan to become pregnant must discontinue it & undergo an 8 day course of cholestyramine elmination therapy prior to conception [7] Dosage: 1) loading dose: 100 mg PO QD for 3 days. 2) maintenance dose: 20 mg PO QD. 3) dose may be reduced to 10 mg PO QD if adverse effects 4) co-administration of folate unneccessay Tabs: 10, 20, 100 mg. Pharmacokinetics: 1) treatment effect generally evident in 1 month & stable in 6 months 2) very long 1/2life [8]; active metabolite may persist for 2 years Monitor: - baseline - CBC, LFTs, serum creatinine - chest X-ray - thereafter - CBC & serum creatinine every 3 months - LFTs every 2-3 months - discontinue for 2-fold elevation of LFTs - add cholestyramine for > 3-fold elevation of LFTs [7] - use with methotrexate requires monthly monitoring of serum AST, serum ALT, & serum albumin [9] Adverse effects: 1) common (> 10%) - diarrhea - rash 2) less common (5-10%) - elevation of serum transaminases (20%) [7] - generally reversible with discontinuation or dose reduction 3) uncommon - pulmonary toxicity - no increase in risk for adverse pulmonary events in patients with rheumatoid arthritis [11] - myelosuppression - agranulocytosis - hepatitis - abdominal pain - fatigue - dark urine - jaundice - at least 130 cases, including 14 deaths [5,10] - cirrhosis - alopecia - hypertension [5] - lymphoma [5] - peripheral neuropathy [7] (uncommon) - axonal, may include sensory, motor or mixed findings [7] - generally self-limited if leflunomide discontinued [7] 4) overall rate of serious adverse effects 19%, similar to methotrexate [3] 5) teratogenic (see contraindications) Toxicity: 1) elimination 1/2 life may be reduced from 16 days to 1 day by administration of cholestyramine 8 g QD 5-11 days 2) activated charcoal may help absorb active metabolite Drug interactions: 1) rifampin increases leflunomide levels by 40% 2) erythromycin is suspect 3) ketoconazole is suspect 4) other hepatotoxic drugs may increase hepatotoxicity a) methotrexate b) NSAIDs 5) leflunomide may increase effect of warfarin [6] -> effect may be seen with a few days Laboratory: - leflunomide in serum/plasma Mechanism of action: 1) appears to work by causing lymphocyte cell cycle arrest in G1 through inhibiting of uridine synthesis at the step catalyzed by dihydro-orotate dehydrogenase* 2) antiproliferative 3) effectiveness similar or somewhat better than methotrexate [3] * replicating lymphocytes lack pyrimidine salvage pathways [7]

General

disease-modifying antirheumatic agent (DMARD) enzyme inhibitor

Properties

INHIBITS: dihydroorotate dehydrogenase, mitochondrial tyrosine kinase MISC-INFO: elimination route LIVER 1/2life 16 DAYS protein-binding 95% elimination by hemodialysis -

Database Correlations

PUBCHEM correlations

References

  1. Internal Medicine Alert 20(22):174 1998
  2. Prescriber's Letter 8(6):32 2001
  3. Journal Watch 21(22):181, 2001 Cohen et al, Arthritis Rheum 44:1984, 2001 Kremmer JM, Ann Intern Med 134:695, 2001
  4. Prescriber's Letter 9(3):13 2002
  5. Prescriber's Letter 9(5):26-27 2002
  6. Prescriber's Letter 10(2):7 2003
  7. Medical Knowledge Self Assessment Program (MKSAP) 15, 17, 18, 19. American College of Physicians, Philadelphia 2009, 2015. 2018, 2022.
  8. Arava Safety Information Prescriber's Letter 11(1):5 2004 Detail-Document#: 200111 (subscription needed) http://www.prescribersletter.com
  9. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  10. FDA MedWatch, 07/13/2010 Arava (leflunomide): Boxed Warning - Risk of Severe Liver Injury http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm218912.htm
  11. Conway R, Low C, Coughlan RJ, O'Donnell MJ, Carey JJ. Leflunomide use and risk of lung disease in rheumatoid arthritis: A systematic literature review and metaanalysis of randomized controlled trials. J Rheumatol. 2016 May;43(5):855-60 PMID: 26980577
  12. Richards BL, Spies J, McGill N et al Effect of leflunomide on the peripheral nerves in rheumatoid arthritis. Intern Med J. 2007 Feb;37(2):101-7. PMID: 17229252