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.

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

Not an MD