leflunomide; teriflunomide (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]
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
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 Medical Knowledge Self Assessment Program (MKSAP) 15, 17, 18, 19. American College of Physicians, Philadelphia 2009, 2015. 2018, 2022.
- ↑ 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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/17229252