Safety evaluation of leflunomide in rheumatoid arthritis

Expert Opinion on Drug Safety

Volumn 12, Issue 4, 2013, Pages 581-588

  Keen, Helen I ^a   Conaghan, Philip G ^b   Tett, Susan E ^c  

^a UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

^b UNIVERSITY OF LEEDS   (United Kingdom)

^c UNIVERSITY OF QUEENSLAND   (Australia)

Author keywords

Leflunomide; Rheumatoid arthritis; Toxicity

Indexed keywords

A 77 1726; ADALIMUMAB; CERTOLIZUMAB PEGOL; ETANERCEPT; GOLIMUMAB; INFLIXIMAB; LEFLUNOMIDE; METHOTREXATE; RECOMBINANT INTERLEUKIN 1 RECEPTOR BLOCKING AGENT; TERIFLUNOMIDE; UNCLASSIFIED DRUG;

ABDOMINAL PAIN; ALLERGIC REACTION; ALOPECIA; COUGHING; DATA BASE; DIARRHEA; DRUG EFFICACY; DRUG ERUPTION; DRUG MARKETING; DRUG MECHANISM; DRUG SAFETY; DRUG STRUCTURE; DRUG SURVEILLANCE PROGRAM; DYSPNEA; GASTROINTESTINAL DISEASE; HUMAN; HYPERHIDROSIS; HYPERTENSION; INFECTION; LIVER FUNCTION TEST; MONOTHERAPY; MOUTH ULCER; NAUSEA; PHARMACOGENOMICS; POSTMARKETING SURVEILLANCE; RECTUM HEMORRHAGE; REVIEW; RHEUMATOID ARTHRITIS; SIDE EFFECT; STEADY STATE; TREATMENT INDICATION; URTICARIA; VOMITING; WEIGHT REDUCTION;

ANIMALS; ANTIRHEUMATIC AGENTS; ARTHRITIS, RHEUMATOID; CLINICAL TRIALS, PHASE II AS TOPIC; CLINICAL TRIALS, PHASE III AS TOPIC; HUMANS; ISOXAZOLES;

EID: 84879364732     PISSN: 14740338     EISSN: 1744764X     Source Type: Journal    
DOI: 10.1517/14740338.2013.798299     Document Type: Review

References (51)

1. Rozman B. Clinical pharmacokinetics of leflunomide. Clin Pharmacokinet 2002;41:421-30 (Pubitemid 34753679)
2. Williams JW, Mital D, Chong A, et al. Experiences with leflunomide in solid organ transplantation. Transplantation 2002;73:358-66 (Pubitemid 34174284)
3. Mrowka C, Thoenes GH, Langer KH, Bartlett RR. Prevention of the acute graft-versus-host disease (GVHD) in rats by the immunomodulating drug leflunomide. Ann Hematol 1994;68:195-9 (Pubitemid 24163529)
4. Eber E, Uhlig T, McMenamin C, Sly PD. Leflunomide, a novel immunomodulating agent, prevents the development of allergic sensitization in an animal model of allergic asthma. Clin Exp Allergy 1998;28:376-84 (Pubitemid 28125924)
5. Osiri M, Shea B, Welch V, et al. Leflunomide for the treatment of rheumatoid arthritis. Cochrane Database Syst Rev 2002(3):CD002047
6. Mladenovic V, Domljan Z, Rozman B, et al. Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis. Results of a randomized, placebo-controlled, phase ii study. Arthritis Rheum 1995;38:1595-603
7. Smolen JS, Kalden JR, Scott DL, et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European leflunomide study group. Lancet 1999;353(9149):259-66 (Pubitemid 29088117)
8. Strand V, Cohen S, Schiff M, et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide rheumatoid arthritis investigators group. Arch Intern Med 1999;159:2542-50
9. Sharp JT, Strand V, Leung H, et al. Treatment with leflunomide slows radiographic progression of rheumatoid arthritis: results from three randomized controlled trials of leflunomide in patients with active rheumatoid arthritis. Leflunomide rheumatoid arthritis investigators group. Arthritis Rheum 2000;43:495-505 (Pubitemid 30394939)
10. Behrens F, Finkenwirth C, Pavelka K, et al. Leflunomide in psoriatic arthritis: results from a large European prospective observational study. Arthritis Care Res 2013;65:464-70
11. Li J, Yao H, Jin Y, et al. Pharmacokinetics of leflunomide in chinese healthy volunteers. Acta Pharmacol Sin 2002;23:551-5 (Pubitemid 34602097)
12. Chong AS, Huang W, Liu W, et al. In vivo activity of leflunomide: pharmacokinetic analyses and mechanism of immunosuppression. Transplantation 1999;68:100-9 (Pubitemid 29352839)
13. Weinblatt M, Kremer J, Coblyn J, et al. Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. Arthritis Rheum 1999;42:1322-8 (Pubitemid 30265588)
14. Shi J, Kovacs S, Wang Y, et al. Population pharmacokinetics of the active metabolite of leflunomide in pediatric subjects with polyarticular course juvenile rheumatoid arthritis. J Pharmacokinet Pharmacodyn 2005;32:419-39 (Pubitemid 41738434)
15. Chan V, Charles BG, Tett SE. Population pharmacokinetics and association between A77 1726 plasma concentrations and disease activity measures following administration of leflunomide to people with rheumatoid arthritis. Br J Clin Pharmacol 2005;60:257-64 (Pubitemid 41224133)
16. Grabar P, Grabnar I, Rozman B, et al. Investigation of the influence of CYP1A2 and CYP2C19 genetic polymorphism on 2-cyano-3-hydroxy-n-[4- (trifluoromethyl)phenyl]-2-butenamide (A77 1726) pharmacokinetics in leflunomide-treated patients with rheumatoid arthritis. Drug Metab Dispos 2009;37:2061-8
17. van Roon E, Jansen T, van de Laar M, et al. Therapeutic drug monitoring of A77 1726, the active metabolite of leflunomide: serum concentrations predict response to treatment in patients with rheumatoid arthritis. Ann Rheum Dis 2005;64:569-74 (Pubitemid 40469086)
18. Grabar P, Rozman B, Tomsic M, et al. Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients. Eur J Clin Pharmacol 2008;64:871-6
19. Roberts LJ, Cleland LG, Thomas R, Proudman SM. Early combination disease modifying antirheumatic drug treatment for rheumatoid arthritis. Med J Aust 2006;184:122-5 (Pubitemid 43256913)
20. Landewe RB, Boers M, Verhoeven AC, et al. Cobra combination therapy in patients with early rheumatoid arthritis: Long-term structural benefits of a brief intervention. Arthritis Rheum 2002;46:347-56 (Pubitemid 34136571)
21. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the best study): a randomized, controlled trial. Arthritis Rheum 2008;58(Suppl 2):S126-35
22. van der Kooij SM, de Vries-Bouwstra JK, Goekoop-Ruiterman YP, et al. Limited efficacy of conventional DMARDs after initial methotrexate failure in patients with recent onset rheumatoid arthritis treated according to the disease activity score. Ann Rheum Dis 2007;66:1356-62 (Pubitemid 47492481)
23. Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010;69:964-75
24. Singh JA, Furst D, Saag KG. 2012 update of the 2008 ACR recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of ra: reply to letter by Graudal et al. Arthritis Care Res 2012;24(10):21872
25. Chan V, Tett SE. Changes in use of disease-modifying anti-rheumatic drugs in australia over the period 1992-2004. Pharmacoepidemiol Drug Saf 2006;15:462-8 (Pubitemid 44150868)
26. Emery P, Breedveld FC, Lemmel EM, et al. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology 2000;39:655-65 (Pubitemid 30459953)
27. Scott DL, Smolen JS, Kalden JR, et al. Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine. Ann Rheum Dis 2001;60:913-23 (Pubitemid 32885664)
28. Nam JL, Winthrop KL, van Vollenhoven RF, et al. Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA. Ann Rheum Dis 2010;69:976-86
29. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59:762-84 (Pubitemid 351847559)
30. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res 2012;64:625-39
31. Golicki D, Newada M, Lis J, et al. Leflunomide in monotherapy of rheumatoid arthritis: meta-analysis of randomized trials. Pol Arch Med Wewn 2012;122:22-32
32. van Riel PL, Smolen JS, Emery P, et al. Leflunomide: a manageable safety profile. J Rheumatol Suppl 2004;71:21-4 (Pubitemid 38703144)
33. Sanofi Aventis US: Arava. Available from: http://www.accessdata.fda.gov/ drugsatfda-docs/label/2010/020905s020lbl.pdf
34. Shankaranarayana S, Barrett C, Kubler P. The safety of leflunomide. Aust Perscriber 2013;36:28-31
35. FDA drug safety communication: new boxed warning for severe liver injury with arthritis drug aava (leflunomide). Available from: www.fda.gov/Drugs/ DrugSafety/PostmarketDrugSafety InformationforPatientsandProviders/ucm218679.htm
36. Sato T, Inokuma S, Sagawa A, et al. Factors associated with fatal outcome of leflunomide-induced lung injury in japanese patients with rheumatoid arthritis. Rheumatology 2009;48:1265-8
37. Sawada T, Inokuma S, Sato T, et al. Leflunomide-induced interstitial lung disease: prevalence and risk factors in japanese patients with rheumatoid arthritis. Rheumatology 2009;48:1069-72
38. Suissa S, Hudson M, Ernst P. Leflunomide use and the risk of interstitial lung disease in rheumatoid arthritis. Arthritis Rheum 2006;54:1435-9
39. Chikura B, Lane S, Dawson JK. Clinical expression of leflunomide-induced pneumonitis. Rheumatology 2009;48:1065-8
40. Savage RL, Highton J, Boyd IW, Chapman P. Pneumonitis associated with leflunomide: a profile of New Zealand and Australian reports. Intern Med J 2006;36:162-9
41. Jenks KA, Stamp LK, O'Donnell JL, et al. Leflunomide-associated infections in rheumatoid arthritis. J Rheumatol 2007;34:2201-3 (Pubitemid 350076879)
42. Carulli MT, Davies UM. Peripheral neuropathy: an unwanted effect of leflunomide? Rheumatology 2002;41:952-3
43. Cutolo M, Bolosiu H, Perdriset G. Efficacy and safety of leflunomide in DMARD-naive patients with early rheumatoid arthritis: comparison of a loading and a fixed-dose regimen. Rheumatology 2013; Epub ahead of print
44. Siva C, Eisen SA, Shepherd R, et al. Leflunomide use during the first 33 months after food and drug administration approval: experience with a national cohort of 3,325 patients. Arthritis Rheum 2003;49:745-51 (Pubitemid 37523625)
45. Bergner R, Peters L, Schmitt V, Loffler C. Leflunomide in dialysis patients with rheumatoid arthritis-a pharmacokinetic study. Clin Rheumatol 2013;32:267-70
46. Cassina M, Johnson DL, Robinson LK, et al. Pregnancy outcome in women exposed to leflunomide before or during pregnancy. Arthritis Rheum 2012;64:2085-94
47. Therapeutic Goods Administration Database of Adverse Events. Available from: www.tga.goc.au/daen
48. Chan V, Tett SE. How is leflunomide prescribed and used in australia? Analysis of prescribing and adverse effect reporting. Pharmacoepidemiol Drug Saf 2006;15:485-93 (Pubitemid 44150871)
49. Bettembourg-Brault I, Gossec L, Pham T, et al. Leflunomide in rheumatoid arthritis in daily practice: treatment discontinuation rates in comparison with other DMARDs. Clin Exp Rheumatol 2006;24:168-71 (Pubitemid 43826866)
50. Bird P, Griffiths H, Tymms K, et al. The SMILE study-safety of methotrexate in combination with leflunomide in rheumatoid arthritis. J Rheumatol 2013;40:228-35
51. van der Velde G, Pham B, Machado M, et al. Cost-effectiveness of biologic response modifiers compared to disease-modifying antirheumatic drugs for rheumatoid arthritis: a systematic review. Arthritis Care Res 2011;63:65-78