REVIEW - Benefit-risk assessment of Arava: an appraisal of Arava in RA 10 years after licensing

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Drug Saf. 2009;32(12):1123-34. doi: 10.2165/11316650-000000000-00000.

Benefit-risk assessment of leflunomide: an appraisal of leflunomide in

rheumatoid arthritis 10 years after licensing.

Alcorn N, Saunders S, Madhok R.

The Centre for Rheumatic Diseases, Glasgow Royal Infirmary, Glasgow, UK.

Evidence is accumulating for the early sustained usage of

disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid

arthritis. Leflunomide was licensed for the treatment of rheumatoid

arthritis in 1998. Postmarketing surveillance, case reports and

observational studies have highlighted less common or unexpected

adverse events. Therefore, it is appropriate that we review the

benefit-risk profile of leflunomide after 10 years of widespread

usage. A wide-based search of relevant literature was performed to

formulate this assessment. The improvements in rheumatoid arthritis

shown by double-blind, randomized controlled trials (RCTs) of

leflunomide have now been shown to be maintained beyond 4 years in

open-label extension studies. Leflunomide is comparable to

methotrexate, but better than sulfasalazine at 24 months in only one

study. However, tolerance in clinical practice research shows higher

than expected withdrawal rates due to both toxicity and lack of

efficacy when compared with methotrexate and placebo.

Adverse events reported include gastrointestinal upset, hypertension,

headache, hepatotoxicity and hair loss, as well as predisposition to

infection and peripheral neuropathy. The incidence of gastrointestinal

adverse effects for leflunomide is similar to sulfasalazine but higher

than those seen with methotrexate. Serious drug-induced hepatotoxicity

leading to hospitalization is rare (0.02%), but isolated fatalities

from liver failure have been documented. It is considered likely, but

not yet proven, that there may be an increased incidence of weight

loss and interstitial lung disease with leflunomide. Leflunomide in

combination with methotrexate or sulfasalazine is an effective regimen

in RCTs utilizing placebo controls, but more research is needed to

confirm its effectiveness in combination with other DMARDs,

particularly biologicals.

The active metabolite of leflunomide is teratogenic in animal studies

and is also found in breast milk. Therefore, contraception is advised

in both males and females of child-bearing potential. There are

genetic, pharmacokinetic and biochemical reasons to explain variation

in both patient response and adverse event profile. Hence, blood and

blood pressure monitoring are recommended and therapeutic drug

monitoring should be considered in clinical nonresponders. Leflunomide

is an effective DMARD that sustains a clinical and radiological

response comparable to sulfasalazine and methotrexate. However,

adverse effects necessitate frequent monitoring. It should be used

with caution in those of child-bearing potential and with pre-existing

lung and liver disease.

PMID: 19916579

http://www.ncbi.nlm.nih.gov/pubmed/19916579

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