leflunomide (Arava)
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Introduction
Tradname: Arava. Pressure from Public Citizen on FDA to remove Arava from US market.
Indications
- rheumatoid arthritis[7]
- may be used concurrently with NSAIDs & low-dose glucocorticoids
- 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]
- ok for use by women on daily oral contraceptive[7]
Dosage
- loading dose: 100 mg PO QD for 3 days.
- maintenance dose: 20 mg PO QD.
- dose may be reduced to 10 mg PO QD if adverse effects
- co-administration of folate unneccessay
Tabs: 10, 20, 100 mg.
Pharmacokinetics
- treatment effect generally evident in 1 month & stable in 6 months
- very long 1/2life[8]; active metabolite may persist for 2 years
elimination via liver
1/2life = 16 days
protein binding = 95 %
elimination by hemodialysis = -
Monitor
- baseline
- 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
- common (> 10%)
- less common (5-10%)
- elevation of serum transaminases (20%)[7]
- generally reversible with discontinuation or dose reduction
- elevation of serum transaminases (20%)[7]
- 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)
- pulmonary toxicity
- overall rate of serious adverse effects 19%, similar to methotrexate[3]
- teratogenic (see contraindications)
Toxicity:
- elimination 1/2 life may be reduced from 16 days to 1 day by administration of cholestyramine 8 g QD 5-11 days
- activated charcoal may help absorb active metabolite
Drug interactions
- rifampin increases leflunomide levels by 40%
- erythromycin is suspect
- ketoconazole is suspect
- other hepatotoxic drugs may increase hepatotoxicity
- leflunomide may increase effect of warfarin[6]
- effect may be seen with a few days
Laboratory
Mechanism of action
- appears to work by causing lymphocyte cell cycle arrest in G1 through inhibiting of uridine synthesis at the step catalyzed by dihydro-orotate dehydrogenase*
- antiproliferative
- effectiveness similar or somewhat better than methotrexate[3]
* replicating lymphocytes lack pyrimidine salvage pathways[7]
More general terms
References
- ↑ Internal Medicine Alert 20(22):174 1998
- ↑ Prescriber's Letter 8(6):32 2001
- ↑ 3.0 3.1 3.2 Journal Watch 21(22):181, 2001 Cohen et al, Arthritis Rheum 44:1984, 2001 Kremmer JM, Ann Intern Med 134:695, 2001
- ↑ Prescriber's Letter 9(3):13 2002
- ↑ 5.0 5.1 5.2 5.3 Prescriber's Letter 9(5):26-27 2002
- ↑ 6.0 6.1 Prescriber's Letter 10(2):7 2003
- ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 Medical Knowledge Self Assessment Program (MKSAP) 15, 17, 18, 19. American College of Physicians, Philadelphia 2009, 2015. 2018, 2022.
Medical Knowledge Self Assessment Program (MKSAP) 20 American College of Physicians, Philadelphia 2025 - ↑ 8.0 8.1 Arava Safety Information Prescriber's Letter 11(1):5 2004 Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=200111&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 9.0 9.1 Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=260704&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 10.0 10.1 FDA MedWatch, 07/13/2010 Arava (leflunomide): Boxed Warning - Risk of Severe Liver Injury http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm218912.htm
- ↑ 11.0 11.1 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: https://pubmed.ncbi.nlm.nih.gov/26980577
- ↑ 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: https://pubmed.ncbi.nlm.nih.gov/17229252