REVIEW - Benefit-risk assessment of leflunomide: an appraisal 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.

Abstract

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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