Leflunomide (Arava): time to change prescribing recommendations?

November 29, 2004

Nov 29, 2004

Derby, UK - Many rheumatologists are routinely disregarding a lot of the prescribing recommendations for the disease-modifying antirheumatic drug (DMARD) leflunomide (Arava, Aventis), a new survey of British specialists shows.

Infrequent use of a loading dose, failure to recommend that patients avoid alcohol completely while taking the drug, not using a washout to transfer patients from leflunomide to another DMARD, and combining the drug with methotrexate were among the bad habits demonstrated in the survey, conducted by Drs S Rajakulendran and C Deighton (Derby Royal Infirmary, UK) and reported in the November 2004 issue of Rheumatology [ 1 ].

"These discrepancies between clinical practice and the recommendations of the summary of product characteristics [SPC] can be interpreted in 2 ways," say Rajakulendran and Deighton.

"The first interpretation is that the SPC is too restrictive, and increasing experience with the drug is influencing confidence in deviating from recommendations." The other way to view this is that consultants have become too relaxed in their approach to the prescribing and monitoring of leflunomide, they suggest.

Half of all respondents disregard prescribing recommendations

Rajakulendran and Deighton sent questionnaires to 72 consultant rheumatologists in the Midlands area of the UK to evaluate the current prescribing practice with leflunomide. The survey asked about the following: the preferential hierarchy of DMARDs in practice and the place of leflunomide; the initiation of leflunomide and whether the loading dose of 100 mg for 3 days was used; advice on alcohol consumption; use of a washout procedure on changing leflunomide to another DMARD; use of combination therapy with methotrexate; and the frequency of monitoring blood and blood pressure.

The results of the survey were compared with the recommendations in the most recent summary of product characteristics for leflunomide.

There were 57 (79%) rheumatologists who returned the questionnaire. Of these, 3 did not prescribe leflunomide. Almost half of the responders who prescribed leflunomide used it as the third drug in their typical DMARD hierarchy, while 17% used it as the second DMARD.

Of the prescribers, 41% never used the loading dose, 22% usually did, 26% usually did not, and 11% always did. The main factors influencing caution in using the loading dose were gastrointestinal side effects and other toxicity. Some consultants adopted a starting dose of 10 mg/day, increasing to 20 mg/day if tolerated.

Interestingly, almost 60% of consultants advised patients that occasional alcohol consumption was acceptable, with many commenting that patients might refuse leflunomide if there were an alcohol ban. Of the others, 22% advised no alcohol restriction, and only 18.5% followed the recommendation of the SPC of avoiding alcohol.

Against SPC recommendations, almost 50% never used a cholestyramine or activated-charcoal washout for swapping leflunomide to another DMARD and 30% used one occasionally.

Some commented that they used shorter washout periods than the recommended 11 days as few patients could tolerate this length of time.

Although the SPC warns against combination therapy, nearly 60% of respondents combined leflunomide with methotrexate occasionally, and 15% did so "usually." Combination therapy was never used by a quarter of the rheumatologists.

In keeping with SPC recommendations, 65% monitored blood biweekly in the first 6 months. The remainder had variable monitoring regimes. Blood pressure was measured biweekly or monthly by most of the respondents.

Enough data to modify SPC for leflunomide

In summary, this survey has demonstrated that for most rheumatologists in the Midlands leflunomide has established a firm footing in their clinical practice and usually follows the failure of sulfasalazine and methotrexate, say Rajakulendran and Deighton.

They believe that "urgent attention needs to be given to modifying the SPC" rather than worrying that consultants having become too relaxed in their approach to using leflunomide.

There are already data on the safe and efficacious use of combinations of leflunomide and methotrexate, despite warnings about possible adverse liver reactions, they note. In addition, full blood-count abnormalities are infrequent, "suggesting that fortnightly blood tests for 6 months is excessive."

We believe that for leflunomide there are already enough data and a sufficient groundswell of clinical practice and experience to modify the SPC.

Meanwhile, more information is required on the efficacy and toxicity of using or avoiding the loading dose, on the safety of alcohol with leflunomide, and on the need for washing patients out before switching from leflunomide to another DMARD, they state.

"The difficulty with SPCs is that, once a recommendation has been made, evidence is needed before it can be modified with confidence. We believe that for leflunomide there are already enough data and a sufficient groundswell of clinical practice and experience to modify the SPC," they conclude.


1. Rajakulendran S and Deighton C. Do guidelines for the prescribing and monitoring of leflunomide need to be modified? Rheumatology 2004; 43:1447-1448.